SmartTots Newsletter

Archived Articles

This SmartTots newsletter, published bimonthly, provides a synopsis of the latest clinical and preclinical pediatric anesthetic neurotoxicity research articles.  IARS staff continually screen newly published peer-reviewed articles from respected journals to identify those of greatest scientific relevance to anesthesiologists, intensivists, related specialists, investigators, parents and the public. Our open-access newsletter provides a link to each highlighted article along with a short summary of key points.

2019 Archive

November Newsletter

Scientific Advisory Board Clinical Working Group

Look for us during 2020 at the following events:

  • SPA/AAP Pediatric Anesthesiology 2020, February 28th – March 1st, 2020, Paradise Island, Bahamas

Tuesday, 12/3 is Giving Tuesday and SmartTots needs your help!

As you read through this newsletter and catch up on the latest scientific research, you will be reminded that important anesthetic neurotoxicity investigations continue in both the preclinical and clinical arenas. The research and debate of this critical issue carries on simply because the best available data remain inconclusive. SmartTots continues to accelerate its efforts to fund research to identify and lessen the risks for children. However, we need your help. And thanks to a very generous SmartTots benefactor, every dollar that you donate will be matched by 50 cents.

Learn how you can help at

Survey: Who are today’s Thought Leaders in Pediatric Anesthesiology?

We would like your opinion on who you consider to be the thought leaders in pediatric anesthesiology — please take a few moments to share your thoughts by completing a quick, 2-question survey online.

Please complete the survey by November, 29 at:

Research News & Updates

Anesthesia Neurotoxicity in the Developing Brain: Basic Studies Relevant for Neonatal or Perinatal Medicine. Clausen, Hansen, & Disma. December 2019

Investigators present known and suspected mechanisms of anesthesia-induced neurotoxicity and discuss the difficulties in translating findings from animals to humans. When is a child’s developing brain most vulnerable to anesthesia exposure? What interventions are neurotoxic? What is neuroprotective? How will scientists find the answers to these questions given the ethical issues in pediatric research?

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Human Studies of Anesthesia-Related Neurotoxicity in Children: A Narrative Review of Recent Additions to the Clinical Literature. O’Leary JD. December 2019

In their review, researchers explore reassuring findings in recent human studies on anesthesia-induced pediatric neurotoxicity. There is now strong evidence supporting no detectable neurocognitive injury after a single, short exposure to anesthesia. Do these findings also apply to children at high risk for neurologic injury after anesthesia? This remains unclear.

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Beyond Anesthesia Toxicity: Anesthetic Considerations to Lessen the Risk of Neonatal Neurological Injury. McCann, Lee, & Inder. November 2019

The review summarizes the main types of brain injury in high-risk, preterm and term infants with an in depth look at potentially modifiable neurotoxic and pathogenic pathways. The authors urge anesthesiologists to avoid perioperative risk factors that can increase brain injury. These include hypotension and hypertension, hypo- and hypercapnia, hypoglycemia, hyper- and hypoxia, hypothermia and hyperthermia, and malpositioning of the infant.

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Sedation practices in pediatric patients with acute lymphoblastic leukemia. Nugent, Davis, Noll, & Tersak. October 2019

Investigators survey The Children’s Oncology Group–experts in childhood cancers from around the world–about sedation practices for lumbar puncture, LP, in children with acute lymphoblastic leukemia, ALL. Findings reveal a substantial number of children with ALL do receive sedation for LP. Propofol is the most common sedation agent, but sedation practices differ among institutions. More research is needed to clarify the safest LP sedation agents/methodologies given growing concern about late-effect, anesthesia-induced neurocognitive deficits.

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Influence of general anesthetic exposure in developing brain on cognition and the underlying mechanisms. Zhao, Ha , Zhang YT, Zhang Y, & Zhang C. October 2019

The authors provide an update on the pathophysiologic mechanisms of anesthesia-induced neurotoxicity in this review of animal and human studies. Findings show a single, short-term exposure to general anesthesia does not affect nervous system function while multiple exposures may damage cognitive function. Exposure to general anesthesia can induce intracellular calcium overload; disturb energy metabolism; promote brain cell death; damage synaptic structure, and impair brain function. The developmental time point of anesthesia exposure is more critical than the duration of exposure.

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General anesthetic neurotoxicity in the young: Mechanism and prevention. Ji, Ni, Chen, Yang, & Ma. October 2019

In their review, the authors explore neurological outcomes after general anesthesia in young children. The investigation delves into mechanistic and epigenetic data on anesthetic exposure as it relates to cognitive impairment and preventive strategies, including herbal compounds. These and other medications may have the potential to reduce side effects and treat neurotoxicity—but they need further study.

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Epigenetic Alterations in Anesthesia-Induced Neurotoxicity in the Developing Brain. Wu & Zhao. July 2018

This review explores the role of epigenetic mechanisms, factors that can influence gene expression levels, in the process of anesthetic neurotoxicity. The authors discuss the therapeutic value of epigenetic changes in DNA methyltransferases and histone deacetylases—enzymes that regulate gene expression, often with aberrant consequences. Epigenetics may be helpful in uncovering novel markers for research in the field of neuroprotection.

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Anesthesia Exposure in the Young Child and Long-term Cognition: An Integrated Review. Rosenblatt, Kremer, Swanson, & Shah. June 2019

In their review, investigators evaluate human research on anesthesia neurotoxicity in children. Findings in several clinical studies show no difference in cognitive function when comparing children with early anesthesia exposure to those with no exposure. Other clinical studies do associate early exposure with lower gray matter density in the brain; lower IQ, listening, language, and academic performance; and a higher risk of learning disability. The authors call for human studies that measure—simultaneously–anesthesia exposure, cognitive function, physical changes, and disability risk.

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Traditional Chinese medicine, Kami-Shoyo-San protects ketamine-induced neurotoxicity in human embryonic stem cell-differentiated neurons through activation of brain-derived neurotrophic factor. Li, Liu, Li, & Wang. November 2019

Investigators explore the neuroprotection of Kami-Shoyo-San, KSS, a Chinese herbal medicine, against ketamine-induced neuronal cell death. Findings show high concentrations of ketamine induce significant brain cell death. Pre-incubation of KSS reduces brain cell death. KSS activates the brain-derived neurotropic factor/tropomyosin receptor kinase B signaling pathway by upregulating brain-derived neurotropic factor (BDNF) and inducing tropomyosin receptor kinase B (TRKB) phosphorylation. Deactivation of the BDNF/TRKB signaling pathway reverses KSS neuroprotection.

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Xenon reduces sevoflurane-induced respiratory depression and neuro-apoptosis in immature rats. Hannah Gill. October 2019

Investigators compare blood gasses and count dead brain cells in neonatal rats exposed to different combinations of sevoflurane, SEVO, and Xenon, a gas with neuroprotective properties. Test groups receive 1) 2.7% SEVO alone, or 2) 1.8% SEVO + 35% Xenon, or 3) .9% SEVO + 70% Xenon. Findings show Groups 1 and 2 with more dead brain cells than Group 3. There is significant improvement with increasing and decreasing doses of Xenon and SEVO, respectively, and no significant difference between those receiving 70% Xenon and controls.

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The expression of glucose transporters and mitochondrial division and fusion proteins in rats exposed to hypoxic preconditioning to attenuate propofol neurotoxicity. Xiao et al. October 2019

The authors explore mechanisms of brain recovery from neurodegeneration in neonatal rats given hypoxic/normoxia preconditioning (HP), during which they breathe 8% and 21% oxygen, followed by propofol, PPF. Findings show PPF damages mitochondria, and reduces glucose transporter 3 and pDrp1 protein expression. HP reduces PPF-induced neurotoxicity by reducing the increase in mitochondrial division and decreasing glucose transporter protein expression.

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Protective Effects of Xenon on Propofol-Induced Neurotoxicity in Human Neural Stem Cell-Derived Models. Liu et al. October 2019

The authors explore the neuroprotective properties of Xenon, a noble gas, in human-derived neural stem cells (hNSCs) differentiated into neurons, astrocytes, and oligodendrocytes. Findings show that propofol (PPF) exposure produces elevated levels of neuronal cell death in hNSCs, but no significant changes to astrocytes and oligodendrocytes. Xenon, when used in combination with PPF, blocks PPF neuronal damage and loss with no significant effects when used alone.

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Immature murine hippocampal neurones do not develop long-term structural changes after a single isoflurane exposure. Tong et al. September 2019

What is the long-term impact of isoflurane, ISO, exposure on granule cells in the hippocampus? Approximately 10% of these cells die after exposure, but what happens to the remaining 90%? To answer, investigators expose male and female mice to ISO, fate-map their two-week-old granule cells, then measure results two months later. Findings show ISO exposure has little effect on gross structure of the dentate gyrus in either sex–no changes in spine density, spine type, dendrite length, or presynaptic axon terminal structure. Individual granule cells remain structurally normal.

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Early exposure to general anesthesia impairs social and emotional development in rats. Diana, Joksimovic, Faisant, & Jevtovic-Todorovic. September 2019

The authors investigate long-term socio-emotional impairments (inattentiveness, ADHD), anxiety/fear, and problematic social behaviors associated with early exposure to general anesthesia, GA. Infant rats receive 1) midazolam + nitrous oxide + isoflurane in oxygen or 2) oxygen + dimethyl sulfoxide (sham), followed by behavioral tests in adolescence and young adulthood. Findings show early exposure to GA results in novelty-seeking tendencies, less guarded behavior, and changes in social discrimination.

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Sevoflurane-Induced Dysregulation of Cation-Chloride Cotransporters NKCC1 and KCC2 in Neonatal Mouse Brain. Cabrera et al. September 2019

What effect does early exposure to sevoflurane, SEVO, have on the balance of NKCC1 (N1) and KCC2 (K2), cation-chloride cotransporters, which help regulate healthy neuronal activity? Investigators find SEVO increases cortical N1 at 6 hours post exposure, decreases cortical/hippocampal K2 at 24 hours, and increases the N1/K1 ratio at 6 and 24 hours. Disruption of the N1/K2 balance may play a key role in circuit hyperexcitability and contribute to neurodevelopmental impairments.

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The Role of Free Oxygen Radicals in Lasting Hyperexcitability of Rat Subicular Neurons After Exposure to General Anesthesia During Brain Development. Joksimovic, DiGruccio, Boscolo, Jevtovic-Todorovic, & Todorovic. September 2019

How does exposure to hydrogen peroxide, H202, a reactive oxygen species (ROS), along with general anesthesia affect neuron excitability in neonatal rat brain slices? Investigators find lower concentrations of H202 excite neurons while higher concentrations inhibit neuronal firing. 0.3 mM H202 increases the action potential frequency of subicular neurons twofold. The increase in ROS after GA exposure may be a key factor in neuron excitability.

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Maternal exposure to volatile anesthetics induces IL-6 in fetal brains and affects neuronal development. Hirotsu et al. September 2019

The authors treat pregnant mice with sevoflurane, SEVO, to determine the effect of pro-inflammatory cytokine molecules, IL-6 and IL-17, on the brains of offspring. Findings show SEVO induces IL-6 mRNA significantly in the fetal brain, but does not upregulate IL-17. Maternal SEVO significantly increases neuronal precursor cells in offspring at 8 weeks after birth, causes learning impairments, and has potentially long-lasting effects on fetal brain development.

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Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia. Zhou et al. August 2019

How does sevoflurane, SEVO, exposure affect astrocytes, brain cells that support nerve connections? Investigators find SEVO compromises the way astrocytes form and develop, enabling synaptic overgrowth and less synaptic function in the cortex. SEVO disrupts astrocyte CA2+ homeostasis leading to down-regulation of Ezrin, an astrocyte-supportive protein. Overexpression of Ezrin inhibits astrocytic and neuronal dysfunction, helping to correct deficits in social behaviors associated with lengthy SEVO exposure.

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Cell cycle activation contributes to isoflurane-induced neurotoxicity in the developing brain and the protective effect of CR8. Huang et al. May 2019

How does the Cyclin B1-mediated cell cycle activation pathway contribute to isoflurane (ISO) induced neurotoxicity? To answer, scientists give CR8 to neonatal mice, to inhibit this pathway, prior to isoflurane (ISO) exposure. Results show a cascade of events triggered by isoflurane exposure in the developing brain, including upregulation of neuronal cell cycle protein Cyclin B1, activation of Cdk1, and phosphorylation of protein Bcl‐xL—all leading to neuronal cell death. CR8 protects against isoflurane‐induced cell cycle activation and neurodegeneration.

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Inhibition of microRNA-375 ameliorated ketamine-induced neurotoxicity in human embryonic stem cell derived neurons. Zhao et al. April 2019

What is the role of human microRNA 375 (375) in regulating ketamine (K)-induced neural cell death and neural toxicity? Using an in vitro model with human embryonic stem cells, investigators find K induces neural death, reactive oxygen species augmentation, neurite degeneration, and upregulates 375. When downregulated, lentivirus-mediated 375 protects K-induced neural cell death and neural toxicity. 375 also directly and inversely regulates brain derived neurotropic factor (BDNF) which, when downregulated, reverses the protective effect of 375 downregulation.

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Neonatal exposure to propofol affects interneuron development in the piriform cortex and causes neurobehavioral deficits in adult mice. Yu et al. February 2019

Investigators explore the effects of early exposure to propofol (PPF) on the neonatal and adult rat brain using c-Fos techniques that map affected neurons. Findings show early PPF exposure leads to significant c-Fos expression in the piriform cortex, particularly in calbindin (CB)-positive interneurons. By adulthood, subjects display impairments in olfactory function, sociability, and recognition skills, along with a significant decrease in the number of CB-positive interneurons.

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September Newsletter

Look for us during 2019 at the following events:

  • Society for Pediatric Anesthesia 33rd Annual Meeting, October 18th, 2019, Orlando, FL
  • American Society of Anesthesiologists, ANESTHESIOLOGY 2019! October 19th – 23rd, 2019, Orlando, FL

Research News & Updates

Anesthetics: from modes of action to unconsciousness and neurotoxicity. Iqbal et al. August 2019

In their review, the authors address the detrimental short and long-term effects of general anesthesia on both the developing and aging brain, as reflected in findings from basic science and clinical research. The discussion includes ways to mitigate the detrimental effects of anesthesia on children and encourages new research aimed at finding better, less toxic anesthetic compounds.

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Anesthesia-induced developmental neurotoxicity in children: past, present, and future. Liu-Jia-Zi Shao, Yi Zou, & Fu-Shan Xue. July 2019

The latest clinical research shows that a single, brief anesthesia exposure in early infancy does not result in neurodevelopmental deficits. However, questions remain regarding the long-term neurocognitive effects of longer and multiple anesthesia exposures in children. The authors urge specialties—particularly anesthesiology, surgery, and neurology—to work together in addressing this lack of knowledge as a critical public health issue for children and pregnant women.

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Lasting effects of general anesthetics on the brain in the young and elderly: “mixed picture” of neurotoxicity, neuroprotection and cognitive impairment. Wu, Zhao, Weng, & Ma. April 2019

This comprehensive review summarizes molecular and cellular mechanisms of anesthetic neurotoxicity in the developing and aging brain. Sources include in vitro research and research in animals, non-human primates, and human children. The article’s content on the developing brain addresses general anesthesia, neurotoxicity, and neuroprotection in hypoxic-ischemic brain injury. The authors call for large-scale observational studies and clinical trials in children on the effects of longer duration general anesthesia that include sensitive outcome measures and tight controls on confounding factors.

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Potential role of the cAMP/PKA/CREB signalling pathway in hypoxic preconditioning and effect on propofol‑induced neurotoxicity in the hippocampus of neonatal rats. Guan et al. August 2019

Hypoxic preconditioning (HPC) helps brain cells survive a lack of oxygen and brain injury. Using neonatal rats exposed to propofol (P), investigators uncover how HPC protects the brain, reduces brain cell death, and affects signaling pathways. Findings show HPC has multiple effects in the hippocampus, including upregulation of cAMP and phosphorylation of CREB. P increases cleaved caspase-3 and Bax by suppressing cAMP-dependent proteins and Bcl-2. HPC prevents P from triggering brain cell death via the cAMP/PKA/CREB signaling pathway.

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Intranasal Administration of Insulin Reduces Chronic Behavioral Abnormality and Neuronal Apoptosis Induced by General Anesthesia in Neonatal Mice. Li et al. July 2019

In this animal study, PN Day 7 mice receive sevoflurane for three hours a day for three days. Findings associate the anesthetic with mild behavioral abnormalities later is life, including a decrease in brain levels of postsynaptic density 95 (PSD95), a marker for increased brain cell death. Insulin, when given to subjects through the nose before sevoflurane, prevents anesthesia-induced long-term behavioral deficits and the neurotoxic effects on PSD95, thus helping to preserve healthy neurons in the brain.

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Defining the Vulnerability Window of Anesthesia-Induced Neuroapoptosis in Developing Dentate Gyrus Granule Cells – A Transgenic Approach Utilizing POMC-EGFP Mice. Wei et al. July 2019

What is the window for anesthesia-induced neurotoxicity and death in dentate gyrus granule cells of the hippocampus? Investigators expose proopiomelanocortin-enhanced green fluorescent protein, POMC-EGFP, mice at PN Day 21 to sevoflurane, SEVO. Findings show SEVO significantly increases cell death of POMC-ECFP+ granule cells—reflecting a third of all dead cells in the dentate gyrus. The vulnerable window of anesthesia-induced brain cell death extends from the end of the POMC+ stage to the post-POMC+ stage when depolarizing glutamatergic inputs emerge.

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Toxicity mechanism of sevoflurane in neural stem cells of rats through DNA methylation. Wang et al. July 2019

Investigators study the effects of no, low, medium, and high concentrations of sevoflurane (SEVO) on brain cell death and DNA methylation in rat neural stem cells. Findings show increases in SEVO concentrations and exposure times are proportional to increases in rates of cell death and degree of methylation– occurring primarily in autosomes, the non-sex chromosomes. The higher the concentration of SEVO, the higher the degree of methylation, brain cell death, and cell toxicity.

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Overexpression of lncRNA Gm15621 alleviates apoptosis and inflammation response resulting from sevoflurane treatment through inhibiting miR-133a/Sox4. Zhao & Ai. July 2019

Investigators, working with in vitro brain cell cultures, study the role of and interaction among three gene-related factors in sevoflurane (SEVO)-induced neurotoxicity and cognitive disorders. These factors include lncRNA Gm15621 (GM), miR-133a (133), and Sox4 (Sox). Findings show GM can reduce SEVO-induced neurotoxicity and SEVO exposure can decrease GM expression. When overexpressed, GM reduces brain cell death, cell survival rates, and inflammatory response. GM regulates 133 as its direct target while 133’s downstream target is Sox. The GM/133/Sox axis plays a key role in anesthesia-induced cognitive disorders.

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Knockdown of lncRNA MALAT1 alleviates bupivacaine-induced neurotoxicity via the miR-101-3p/PDCD4 axis. Zhao & Ai. June 2019

The authors use in vitro neonatal mouse neurons to clarify the mechanism of bupivacaine (BV) neurotoxicity in lncRNA MALAT1 (M1), a factor in gene expression. Findings show 1) BV elevates expression of M1; 2) knockdown of M1 significantly increases cell death; 3) miR-101-3p (a micro RNA) is the direct target of M1; and 4) M1 may be a decoy to sponge miR-101-3p. Activation of the MALAT1/miR-101-3p/PDCD4 axis protects cells against the neurotoxic effects of bupivacaine treatment.

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17β-Estradiol Treatment Attenuates Neurogenesis Damage and Improves Behavior Performance After Ketamine Exposure in Neonatal Rats. Li et al. June 2019

Can 17β-estradiol (17β), estrogen from a premenopausal ovary, reduce ketamine (K)-induced neurotoxicity and changes in behavior? The authors test PN Day 7 rats and neural stem cells exposed to K and 17β before and after K. Findings show K decreases cell proliferation in the hippocampus, increases brain cell death, and leads to adult cognitive deficits. 17β reduces K-induced changes both in vivo and in vitro. The protection of 17β associates with GSK-3β, an enzyme involved in brain cell division, proliferation, motility, and survival.

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LncRNA MALAT1 is involved in sevoflurane-induced neurotoxicity in developing rats. Xueyan Hu, Xiaodong Hu, & Guirong Huang. June 2019

How does the long chain noncoding RNA metastasis-associated lung adenocarcinoma transcript 1-MALAT1 (M1), a genetic factor associated with cancer in humans and synaptic changes in animals, effect sevoflurane (SEVO)-induced neurotoxicity? Investigators treat PN Day 7 rats with SEVO or MALAT1 small interfering RNA to clarify M1 expression, pathological changes, and neurotoxic effects in the brain. Findings show M1 is highly expressed in the rat hippocampus, but when suppressed can reduce neuronal cell death, increase brain cell density, and improve spatial learning/memory.

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Both GSK-3β/CRMP2 and CDK5/CRMP2 pathways participate in the protection of dexmedetomidine against propofol-induced learning and memory impairment in neonatal rats. Li J et al. June 2019

How does dexmedetomidine (DEX) protect the neonatal rat brain from propofol (P)-induced neurotoxicity? Findings show 50 μg·kg-1 of DEX reduces P-induced brain cell death in hippocampal neurons and astrocytes, and reverses toxic activation of the GSK-3β and CDK5 brain pathways. GSK-3β and CDK5 inhibitors reduce P-induced brain cell death, proliferation inhibition, GABA and glutamate downregulation, and learning/memory dysfunction. DEX inhibits P-induced activation of the GSK-3β/CRMP2 and CDK5/CRMP2 pathways.

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Euxanthone Ameliorates Sevoflurane-Induced Neurotoxicity in Neonatal Mice. Zhou H, Li S, & Wang G. June 2019

Using neonatal rats and in vitro hippocampal neurons, the authors study the neuroprotective qualities of euxanthone (EUX), a plant-derived organic compound. Findings show EUX exposure in the neonatal phase protects against sevoflurane-induced neurotoxicity, when measured in adult rats. In vitro, EUX reduces brain cell death and neuroinflammation, upregulates Nrf2 expression, and helps brain cells fight damaging oxidants. EUX may have potential as a clinical therapy for anesthesia-induced neurotoxicity.

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The positive allosteric modulation of GABAA receptors mRNA in immature hippocampal rat neurons by midazolam affects receptor expression and induces apoptosis. Sinner, Steiner, Malsy, Graf, & Bundscherer. June 2019

The authors use neuronal cell cultures from rat embryos to study the effects of midazolam on brain cell death and neurotransmitters. Findings show midazolam at 100 or 300 nM for 30 minutes or 4 hours has reversible effects on gene expression in some subunits of the glutamate and GABAA receptors. However, 300 nM midazolam for 4 h induces irreversible increases in gene expression within subunits of the glutamate, NMDA, and AMPA receptors. Prolonged increases in glutamate receptor expression associate with brain cell death.

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Role of autophagy in sevoflurane-induced neurotoxicity in neonatal rat hippocampal cells. Xu et al. June 2019

The authors use cultured hippocampal neuron cells from neonatal rat brains to explore the mechanisms of sevoflurane (SEVO)-induced neurotoxicity. How does it involve autophagy, the body’s process of cell clean up, recycling, and renewal? Findings show SEVO exposure may induce autophagy and activate the cell death process in hippocampal neuron cells, alter autophagy proteins, and involve the signaling pathway regulated by the autophagy proteins Beclin-1 and Atg5./p>

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The Neuroprotective Effect of Hemin and the Related Mechanism in Sevoflurane Exposed Neonatal Rats. Yang et al. May 2019

Can hemin, a medication derived from red blood cells, treat sevoflurane (SEVO) – induced neurotoxicity? Scientists test neonatal rats receiving no SEVO, hemin, 3% SEVO, or hemin + SEVO. Findings show SEVO increases expression of cleaved caspase-3, cytochrome c, and Drp1 in the hippocampus—neurotoxic activity that affects healthy brain cell function. Hemin offers neuroprotection against SEVO-induced cognitive impairment by reducing brain cell death, improving mitochondrial dynamics, and increasing expression of neuroglobin, a protective protein.

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Pre-administration of luteoline attenuates neonatal sevoflurane-induced neurotoxicity in mice. Wang Y, Wang C, Zhang Y, Wang G, & Yang H. May 2019

Does luteoline (LUT), a flavonoid found in plants like broccoli, reduce sevoflurane (SEVO)-induced neurotoxicity? Investigators study neonatal mice pretreated with LUT before SEVO exposure. Findings show LUT reduces SEVO-induced brain cell death; inhibits the NF-кB/NLRP3 pathway; and suppresses NF-кB activity. LUT also significantly decreases contents of oxidative stress markers, ROS and MDA; elevates the activity of SOD (an enzyme that helps prevent tissue damage); and ultimately improves spatial learning and memory.

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Neonatal exposure to the experimental environment or ketamine can induce long-term learning dysfunction or overmyelination in female but not male rats. Zhang, Chen, Deng, Wang, & Liu. May 2019

This study explores the effects of multiple early exposures to ketamine on cognitive function in adulthood. Investigators divide male and female neonatal rats into three groups: 1) ketamine injections, 2) saline injections of equal volume to group #1–the “experimental environment”; and 3) control/no injections. Tests include Morris Water Maze for learning/memory and analysis of brain slices after sacrifice. Findings show female, but not male, rats in the experimental environment can develop learning dysfunction in adulthood. Ketamine can increase myelination in the cortex of female rats, but does not induce learning dysfunction in adulthood.

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Relevance of experimental paradigms of anesthesia induced neurotoxicity in the mouse. Johnson et al. March 2019

The clinical significance of preclinical models for anesthesia-induced neurotoxicity remains unclear. To add clarity, the authors conduct a systematic evaluation of critical physiological parameters in PN Day 7 mice exposed to 1.5% isoflurane for 2-4 hours. Findings show 2+ hours of anesthesia results in respiratory and metabolic changes that are too dramatic for interpretation in the clinical setting. Mouse models of anesthesia-induced neurotoxicity are not necessarily good representations of the human experience under anesthesia.

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July Newsletter

Look for us during 2019 at the following events:

  • Society for Neuroscience in Anesthesiology and Critical Care, 47th Annual Meeting, September 12th – 14th, 2019, Phoenix, AZ
  • Society for Pediatric Anesthesia 33rd Annual Meeting, October 18th, 2019, Orlando, FL
  • American Society of Anesthesiologists, ANESTHESIOLOGY 2019! October 19th – 23rd, 2019, Orlando, FL

Research News & Updates

Parental understanding of their child’s risk of anaesthesia. Morrison et al. July 2019

This qualitative, interview-based study explores how parental knowledge of anesthesia risks affects consent for a child’s anesthesia and surgery. Subjects include 211 parents of children averaging 6.6 years of age having same-day, non-emergent surgery. Findings show that no individual risks ultimately affect the parental consent for anesthesia, but the risk of death may affect the decision to proceed with surgery. Nearly half of all parents preferred no further risk discussion on the day of surgery. The authors encourage anesthesiologists to tailor the discussion of pediatric anesthesia risks to each individual parent and child.

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Mayo Anesthesia Safety in Kids continued: two new studies and a potential redirection of the field. Caleb Ing. June 2019

Recent MASK follow up studies find no significant difference in Operant Test Battery, OTB, scores between children who have single or multiple exposures to general anesthesia and those who are unexposed. The authors pose timely questions to their colleagues: Should we conclude that findings in animals have no bearing on children? Is there evidence for anaesthetic exposure and deficits in other outcomes? Will a child exposed to multiple anaesthetics develop neurodevelopmental deficits? Should parents and clinicians be concerned? Are results of MASK follow up studies consistent with previous studies? A next step may be to evaluate more subtle effects of anesthesia, particularly in behavioral and executive function.

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The Effects of Anesthesia on the Pediatric Developing Brain: Strategies to Reduce Anesthesia Use in Pediatric MRI and Nursing’s Role in Driving Patient Safety. Mastro, Flynn, Preuster, Summers-Gibson, & Stein. June 2019

In their literature review of 36 studies, the authors explore patient and family-centered care strategies for, and the role of nurses in, reducing anesthesia and sedation in children having magnetic resonance imaging, MRI. Findings show few studies testing ways to reduce anesthesia and sedation. However, a multipronged yet structured methodology, with an individualized plan to prepare each child for MRI, appears successful. Nurses can play an important role in engaging the patient and family as partners in reducing anesthesia, sedation, and their associated risks.

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Association Between Anesthesia Exposure and Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia.  Banerjee, Rossi, Anghelescu, et al, June 2019

Investigators study the effects of general anesthesia for 5699 anesthetic procedures in 212 children–all survivors of acute lymphoblastic leukemia–at a mean age of 7.7 years post-diagnosis. Neurocognitive impairment associates with higher propofol cumulative dose, flurane exposure, and longer anesthesia duration per hour. Slower processing speed associates with higher propofol dose, a greater number of exposures, and longer anesthesia duration. Higher white matter diffusivity associates with propofol dose and duration of anesthesia. Neurocognitive impairment and neuroimaging abnormalities associate with higher cumulative anesthesia exposure and duration.

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GAS, PANDA, and MASK – No Evidence of Clinical Anesthetic Neurotoxicity Vutskits & Culley, May 2019

The authors highlight reassuring results of the GAS prospective clinical trial, consistent with the PANDA and MASK human studies—that early, short-duration exposure in children to general anesthesia does not alter neurodevelopment. Given a lack of clinical justification, is it time to eliminate the FDA warning on use of anesthesia in young children? Perhaps we are facing the likelihood that developmental neurotoxicity may not exist for the majority of short-duration pediatric surgeries? Questions do remain on the effects of anesthesia in children undergoing longer surgeries as well as the effects of anesthesia on neuroinflammation and perioperative stress.

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Anesthesia for pediatric ophthalmologic surgery. Waldschmidt & Gordon. April 2019

This review provides updates on a number of recommendations for anesthetic management of strabismus surgery in children, performed a majority of the time under general anesthesia. The authors address prevention of post-operative complications and, in light of the 2016 FDA warning, recent studies on pediatric anesthetic neurotoxicity and general anesthesia are discussed. Key topics also include preoperative anxiolysis, fasting guidelines, management of upper respiratory infections, airway considerations, and oculocardiac reflex.

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Combined spinal/caudal catheter anesthesia: extending the boundaries of regional anesthesia for complex pediatric urological surgery. Jayanthi et al. April 2019

The authors conduct a retrospective chart review on a combined spinal/caudal catheter, SCC, technique in pediatric urologic surgery. Subjects include 23 children attempting SCC. Of them, 20 use SCC successfully at a mean age of 16.5 months for an average of 109 minutes in surgery. Spinal anesthesia is unsuccessful in three patients. Findings show no intra-operative or perioperative complications for the 20 completing SCC. The technique allows for more complex pediatric urologic surgery under regional anesthesia than under spinal anesthesia alone; it may reduce the use of opioids and may help avoid risks associated with general anesthesia.

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Propofol induces impairment of mitochondrial biogenesis through inhibiting the expression of peroxisome proliferator-activated receptor-γ coactivator-1α. Qin, Li, & Wang. June 2019

What is the effect of propofol on neuronal mitochondrial function in SH-SY5Y cells? Propofol 1) reduces the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α); 2) suppresses the mitochondrial regulator nuclear respiratory factor 1 and mitochondrial transcription factor A; 3) reduces intracellular adenosine triphosphate (ATP) production, mitochondrial respiratory rate, and increases mitochondrial reactive oxygen species production; and 4) suppresses PGC-1α, the central mediator of propofol-induced impairment of mitochondrial biogenesis and neuronal mitochondrial dysfunction.

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Fentanyl Induces Cerebellar Internal Granular Cell Layer Apoptosis in Healthy Newborn Pigs. Sabir, Dingley, Scull-Brown, Chakkarapani, & Thoresen. May 2019

Does intravenous, IV, fentanyl cause cell death in the cerebellum? To answer, investigators study two groups of newborn pigs: Group #1-IV fentanyl exposure for 24 hours (n=6) and Group #2-the nonventilated control (n=7). Methods include morphological assessment after staining, immuno-staining of paired sections, and cell counting. Group #1 shows a significant increase in brain cell death in the granular cell layer of the cerebellum. There is no difference in the number of Purkinje neuronal cells between groups and other parameters remain comparable and stable.

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Disrupted folate metabolism with anesthesia leads to myelination deficits mediated by epigenetic regulation of ERMN. Zhang et al. May 2019

How does general anesthesia affect folate metabolism and myelination, important to healthy brain development? Findings show that sevoflurane downregulates the thymidylate synthase gene in young monkeys and mice. In mice alone, sevoflurane compromises myelination while folic acid and ERMN gene expression fight back, helping to alleviate anesthesia-induced cognitive impairment. In children, blood folate levels go down after anesthesia and surgery. Investigators conclude that general anesthesia targets the ERMN gene, disrupts folate metabolism, and causes defects in myelination.

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Limb Remote Ischemic Preconditioning Reduces Repeated Ketamine Exposure-Induced Adverse Effects in the Developing Brain of Rats. Liu et al. May 2019

Using newborn rats, investigators explore the neuroprotective potential of remote ischemic limb preconditioning, a technique that may reduce severity of injury to organs and trigger protective actions, against ketamine (KET)-induced neurotoxicity. Investigators divide 96 newborn rats into four groups: 1-a control; 2-remote ischemic preconditioning (RIPC); 3- KET exposure; and 4-RIPC + KET exposure. Findings in groups exposed to KET show an increase in cleaved caspase-3 protein levels in the cerebral cortex, DNA breakage, and a decrease in learning and memory abilities. RIPC significantly reduces these changes and may ameliorate KET-induced brain cell death and neurocognitive impairment.

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Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies. Johnson, Pan, Li, Sedensky, & Morgan. January-February 2019

What mechanisms mediate anesthesia-induced neurotoxicity, AIN, in mice? To answer, the authors provide a review of AIN studies in mice, including interventions tested in vivo and AIN paradigms in neonatal mice. There is no standardization of preclinical models and they often include variable and complex combinations of drugs. Pathways underlying molecular, cellular, and behavioral outcomes are poorly explored. However, data from neonatal mice models strongly implicate three critical AIN pathways: 1) reactive oxygen species (ROS) mediated stress and signaling, 2) growth/nutrient signaling, and 3) direct neuronal modulation.

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May Newsletter

Participants of the recent SmartTots Workshop for Preclinical Research in Anesthetic Neurotoxicity.

The workshop brought together a diverse, multi-disciplinary group of researchers in an effort to develop a common framework for pre-clinical studies. The overarching goal of this workshop was to develop consensus regarding reporting of studies for publication, so that there is comparability and consistency across different laboratories, and discuss future directions for pre-clinical research in anesthetic neurotoxicity in the developing brain. The workshop was a successful step forward in these efforts. Stay tuned for more information about the outcomes of this successful gathering.

Look for us during 2019 at the following events:

  • Society for Neuroscience in Anesthesiology and Critical Care, 47th Annual Meeting, September 12th – 14th, 2019, Phoenix, AZ
  • <Society for Pediatric Anesthesia 33rd Annual Meeting, October 18th, 2019, Orlando, FL
  • American Society of Anesthesiologists, ANESTHESIOLOGY 2019! October 19th – 23rd, 2019, Orlando, FL

Research News & Updates

Patterns of neuropsychological changes after general anaesthesia in young children: secondary analysis of the Mayo Anesthesia Safety in Kids study. Zaccariello et al. May 2019

Is there an association between multiple exposures to general anesthesia in children < 3 years and deficits in processing speed and fine motor skills? To answer, the authors analyze data from the Mask Study. A 5-factor analysis shows multiply-exposed children, when compared to those with single exposure and no exposure, with significantly lower factors in motor skills, visual-motor integration, and processing speed. Cluster analysis yields a specific pattern of deficits in neuropsychological tests. The odds are higher that multiply-exposed children will fall into the lowest test performance cluster.

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Performance on the Operant Test Battery in young children exposed to procedures requiring general anaesthesia: the MASK study. Warner et al. April 2019

Does general anesthesia in children < 3 years impair performance on the Operant Test Battery in the same way it impairs performance in infant macaques? This cluster analysis of data from the MASK Study, of children ages 8-12 or 15-20 years, finds no association between anesthesia exposure and test performance in five task areas. Children with multiple exposures do show significantly lower performance in one test area, but this result disappears after sensitivity analysis.

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Assessing Long-term Neurodevelopmental Outcome Following General Anesthesia in Early Childhood: Challenges and Opportunities. Walkden, Pickering, & Gill. April 2019

What are the weaknesses of methods in pediatric research on the long-term effects of anesthesia on neurodevelopment? The authors identify current challenges: separating the effects of anesthesia from surgery; defining time/duration of exposure; selecting surgical cohorts and interventions; addressing confounding factors; finding modest neurotoxic effects in small samples; selecting age-appropriate outcomes in different developmental domains; and dealing with poor length of follow up and sample attrition. Solutions include strong multicenter clinical trials in parallel with well-designed observational cohort studies.

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Caudal epidural blocks in paediatric patients: a review and practical considerations. Wiegele & Marhofer. April 2019

This literature review presents key findings on caudal epidural block, a common technique for delivering regional anesthesia to children. The authors address patient selection; anatomical and technical considerations; training and equipment requirements; local anesthetics; adjuvant drugs and volume dosing; caudally-accessed lumbar and thoracic anesthesia; and post-op pain. Caudal block has advantages over general anesthesia: it is efficient for sub-umbilical interventions, enables early ambulation and periprocedural haemodynamic stability, and helps with spontaneous breathing for children at risk for difficult airway.

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Anaesthetic neuroprotection in children: does it exist or is it all just bad? Marchesini & Disma. March 2019

The authors summarize a growing body of literature on neuroprotective strategies and solutions, a new area of research, on anesthesia-induced damage to the developing brain. Findings show neuroprotective actions, including pharmacologic protections, can save neuronal structure and function; mitigate neurotoxicity; reduce the effects of cumulative dose; promote neuroplasticity; and reduce pain from surgery. These actions help to preserve cortical activity and brain development. The article highlights solutions that are not yet applicable to clinical practice and encourages further research.

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Effects of Perinatal Exposure to Ketamine on the Developing Brain. Cheung & Yew. February 2019

This article addresses the abuse of ketamine, KET, as a recreational drug and an anti-depressant, and its use/misuse in pregnant women and children. The authors summarize recent research on perinatal KET-induced neurotoxicity, neuroprotective effects, and suggest future actions. These include education and prevention campaigns on the harmful effects of KET; studies to develop KET alternatives; and treatments to reduce the harmful effects of KET in children.

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Neuroinflammation in the Developing Brain: Risk Factors, Involvement of Microglial Cells, and Implication for Early Anesthesia. Baud & Saint-Faust. April 2019

This review looks at the neurotoxic intersection of adverse perinatal events and inflammation, both systemic and neuroinflammation, with microglial cells, which normally support healthy brain function. The authors discuss prematurity; neurodevelopmental impairment; microglial activation and perinatal brain damage; perinatal stress; and anesthesia and microglial reactivity. As the primary target of inflammation in the brain, microglial cells when activated can play a critical role in synaptic and network dysfunction.

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Erythropoietin Reduces Neurodegeneration and Long-Term Memory Deficits Following Sevoflurane Exposure in Neonatal Rats. Goyagi T. April 2019

Scientists study the effects of erythropoietin, EPO, a hormone, on brain cell structure and cognitive function in neonatal rats. Subjects receive 60, 120, or 600 units of EPO followed by 3% sevoflurane and 21% oxygen v. no EPO. The Morris water maze shows significant reductions in escape latency and % time remaining in quadrant in the rats with 600 units of EPO; significant increases in freezing time and NeuN-positive brain cells in the 600 and 120-unit groups; and increases in positive cell density for all EPO groups. As a pretreatment, EPO reduces long-term cognitive deficits and neuronal degeneration associated with sevoflurane and low-oxygen.

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Dexmedetomidine reduced sevoflurane-induced neurodegeneration and long-term memory deficits in neonatal rats. Goyagi T. April 2019

Does dexmedetomidine, DEX, reduce long-term cognitive deficits associated with early exposure to sevoflurane, SEVO? To answer, investigators give neonatal rats SEVO alone v. 6.6, 12.5, or 25 ug/kg of DEX + sevoflurane v. DEX alone, followed by the Morris water maze in adulthood. Subjects with 25 ug/kgs DEX + SEVO show significantly shorter escape latency, a higher percent of time in quadrant, and more NeuN-positive brain cells. The authors conclude that pretreatment with DEX may prevent SEVO-induced cognitive sequelae and neuronal degeneration.

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Quantitative ultrasound and apoptotic death in the neonatal primate brain. Rosado-Mendez et al. April 2019

Using neonatal monkey brains in vivo, the authors detect and measure brain cell death following sevoflurane exposure. Methods include the use of quantitative ultrasound, QUS, and effective scattering size, ESS, a biomarker for QUS, which scans for echo signals. With the exclusion of outlying echo signals, the change in ESS between pre- and post-anesthesia measurements correlates strongly with severity of brain cell death. QUS may enable future in vivo studies of anesthesia-induced cell death in the brains of human infants.

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Female rats are more vulnerable to lasting cognitive impairment after isoflurane exposure on postnatal day 4 than 7. Sasaki Russell, Chinn, Maharjan, Eichbaum, & Sall. April 2019

Do both sex and age play a role in outcome after early exposure to anesthesia? Are females more susceptible to anesthesia-induced injury earlier than males? To answer, researchers expose neonatal rats of both sexes to isoflurane on PN Days 4 or 7 followed by studies on brain cell death, chloride transporter expression, and memory. Day 4 females and Day 7 males show similar, higher ratios of transporter expression than P7 females. The window of vulnerability correlates with sex-specific cortical expression. P4 females show greater brain cell death and memory impairment than P7 females.

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Effects of non-obstetric surgery under ketamine anaesthesia in the middle stage of pregnancy on cognition in the offspring and underlying mechanisms. Feng, Luo, Wang, & Cao. March 2019

Investigators study the effects of maternal ketamine, KET, exposure in mid-pregnancy on cognition in offspring. Pregnant rats receive KET alone v. KET + abdominal surgery v. nothing (control) on Day 14 of gestation. Offspring are tested after birth on PN Days 7, 22, 23, and 30. With KET alone, there is no effect on cognition in offspring. With KET + abdominal surgery, offspring show impairments in spatial perception, spatial learning, and memory. These impairments associate with up-regulation of HDACs (histone deacetylases) activity, down-regulation of protein levels, and the density of dendritic spine.

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Sevoflurane-induced learning deficits and spine loss via nectin-1/corticotrophin-releasing hormone receptor type 1 signalling in neonatal mice. Li, CY Wang, Yu, & GL Wang. March 2019

Using neonatal mice, investigators study changes in nectin-1, a brain protein, after exposure to sevoflurane, SEVO. What are the roles of corticotropin-releasing hormone, CRH, and corticotropin-releasing hormone receptor 1, CRHR1, in SEVO-induced nectin-1 expression changes? Findings show SEVO increases CRH levels, activates CRHR1, and reduces nectin-1 expression. A decrease in the expression of nectin- 1 in the hippocampus can decrease dendritic spine formation and impair learning and memory.

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Isoflurane exposure in infant rats acutely increases aquaporin 4 and does not cause neurocognitive impairment. Demirgan et al. February 2019

Investigators study the effects of isoflurane, ISO, on cognition and expression of aquaporin 4, AQP4, a water channel protein that protects the brain. PN Day 10 rats receive 1.5% ISO in oxygen for 6 hours or oxygen alone followed by tests on PN Days 11 and 28-33. Findings show an ISO-induced increase in mRNA and protein levels of AQP4 on PN Day 11–this may be neuroprotective, but higher levels of AQP4 are no longer evident on Day 33. A single dose of ISO does not affect cognition.

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Dexmedetomidine attenuates the neurotoxicity of propofol toward primary hippocampal neurons in vitro via Erk1/2/CREB/BDNF signaling pathways. Tu et al. February 2019

In their in vitro study, the authors evaluate the cytotoxic effects of propofol, PROP, on hippocampal neurons and test the neuroprotective effects of dexmedetomidine, DEX, as a pretreatment. Findings show PROP reduces cell viability and induces brain cell death; downregulates the expression of BDNF mRNA and levels of phospho-Erk1/2, phospho-CREB, and BDNF proteins. DEX increases neuron viability, reduces PROP-induced neuronal death, and protects these proteins, providing a neuroprotective rescue that selective protein inhibitors, including PD98059, can thwart.

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The Association between attention deficit hyperactivity disorder and general anaesthesia – a narrative review. Xu et al. January 2019

Does early exposure to general anesthesia, GA, predispose a child to attention deficit hyperactivity disorder, ADHD? This review seeks answers in clinical and animal studies relating to ADHD and GA, including studies addressing actions on neural molecular mechanisms and neural networks. The authors also describe potential therapeutic approaches to reduce the toxic effects of GA.

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March Newsletter

IARS achieves GuideStar’s Highest Level of Recognition

IARS and SmartTots are committed to transparency and to maximizing the return on donor support. We are proud to have earned the Platinum Seal from GuideStar, the most trusted and complete source of information about non-profits. The Platinum Seal is GuideStar’s highest level of recognition, demonstrating our focus on measuring progress and results.

Check us out on Guidestar at: As always, 100% of your contributions to IARS or SmartTots go directly to support research.

Look for us during 2019 at the following events:

  • SPA/AAP Pediatric Anesthesiology, March 15 – 17, 2019, Houston, TX
  • IARS Annual Meeting, May 17–20, 2019 Montreal, Quebec, Canada

  • Society for Pediatric Sedation Conference, May 20 – 22, 2019 Aurora, Colorado

Research News & Updates

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. McCann et al. February 2019

Results of the 5-year GAS clinical trial are reassuring and consistent with results of the MASK and PANDA cohort studies. Less than 1 hour (median exposure = 54 minutes) of general anesthesia does not alter neurodevelopmental outcomes compared to awake-regional anesthesia in males, predominantly. The study derives primary outcome data from 205 children with awake-regional and 242 children with general anesthesia in infancy for inguinal herniorrhaphy. There is strong equivalence between the two different anesthesia groups and results are consistent with the GAS 2-year outcomes.

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Neurodevelopment after general anaesthesia in infants, O’Leary & Orser. February 2019

In their commentary, the authors discuss reassuring findings from the GAS 5-year clinical trial while raising a few concerns.  There is a greater-than-expected loss to follow up during the five years with incomplete data for some participants.  Additional contributing factors, other than general anesthesia, need to be considered when generalizing findings.  Study results cannot be extrapolated to children who undergo prolonged or repeated exposures.  Clarifying the dose-dependence of anesthesia-related neurotoxicity requires careful experimental design in future studies, both preclinical and clinical.

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Neurotoxicity of general anesthetics in children: evidence and uncertainties. Bellinger & Calderon. January 2019

In their review, the authors summarize clinical evidence on the neurotoxicity of general anesthesia and sedatives in children, and the associated effects on learning, memory, and behavior. Retrospective studies carry mixed results, but multiple exposures generally show greater neurotoxic risk. Recent randomized control trials confirm that a single exposure of < 1 hour is not associated with neurodevelopmental impairments. Due to clinical necessity, many children have exposures greater > 1 hour thus finding adjuvants to prevent or reduce the potential neurotoxicity is an area of active research.

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Juvenile Rats Show Altered Gut Microbiota After Exposure to Isoflurane as Neonates. Wang, Yang, & Wu. January 2019

Do anesthesia-induced changes in gut microbiota lead to long-term neurocognitive dysfunction? To answer, investigators expose PN Day 7 rodents to 4 hours of isoflurane then examine fecal microbiomes on PN Day 42. Findings show changes in several bacteria taxa at various taxonomic levels. There is a significant increase in Firmicutes, Proteobacteria, Clostridia, Clostridiales, and Lachnospiraceae and a significant decrease in Bacteroidetes, Actinobacteria, Bacteroidia and Bacteroidaceae. These changes provide new insights.

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Neuroprotective effects of dexmedetomidine against isoflurane-induced neuronal injury via glutamate regulation in neonatal rats. Wang, Shan, Tang, Gao, & Liu. December 2018

How does dexmedetomidine, DEX, mitigate isoflurane (ISO)-induced neuronal cell death in neonatal mice? Investigators divide PN Day 7 rats into 4 groups: no ISO, ISO alone, and ISO with single and dual doses of Dex; brain cells were tested at 2 hours-28 days after sacrifice. Findings show Dex protects the brain by regulating NMDAR (a brain receptor that supports healthy cognitive function) subunits NR2A, NR2B, and excitatory amino acid transporter, EAAT1. Protein levels in NR2A, EAAT1, and caspase-3 increase significantly in rats receiving ISO while NR2B levels go down. Dex in single and dual doses mitigates these changes.

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Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway. Bi et al. December 2018

What role does connexin 43, Cx43, (a protein that may contribute to cognitive dysfunction) play in sevoflurane (SEVO)-induced neuroinjury? Investigators expose PN Day 7 rats to 3% SEVO for 4 hours then apply Western Blot Analysis, immunohistochemistry, and the Morris water maze. Findings show SEVO increases Cx43 expression and induces brain cell death by activating the JNK/c-Jun signaling pathway in the brain. Pretreatment with JNK inhibitor, SP600125, alleviates SEVO-induced changes and supports healthy cognitive development.

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Special Newsletter Edition: 2018 PANDA Symposium

The 6th Biennial PANDA Symposium on “Anesthesia and Neurodevelopment in Children” was held at the Morgan Stanley Children’s Hospital of New York on April 14-15, 2018. All of the articles in this Special Edition of the SmartTots Newsletter were published in a supplement of the Journal of Neurosurgical Anesthesiology; they represent summaries of the presentations and related topics at the PANDA Symposium. The PANDA Symposium is hosted by the PANDA Study investigator team. It is a key forum for investigators and other professionals, gathering a diverse group of people with a shared concern about the neurotoxicity of anesthetics to the developing brain as demonstrated in animal studies and the possibility that anesthetics may be neurotoxic to the developing brain in humans. Attendees included clinicians, preclinical and clinical researchers and representatives from the Food and Drug Administration and the National Institutes of Health.

Introduction to “Anesthesia and Neurodevelopment in Children”: A Supplement from the Sixth Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) Symposium. Sun, Lena S. January 2019

The SmartTots Medical Director introduces 13 journal articles, summarized below, from the Sixth PANDA Symposium held in April of 2018. The program included these sessions: 1) Report of the 2017 Outcomes Workshop; 2) Lessons learned: neuroimaging studies and neurodevelopmental outcomes research; 3) Engaging stakeholders to promote safe anesthesia/sedation care in young children; 4) Outcomes research in vulnerable pediatric populations; 5) Developmental neurotoxicity research; and 6) Moderated poster sessions.

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Report on the Sixth Pediatric Anesthesia Neurodevelopmental Assessment (PANDA) Symposium, “Anesthesia and Neurodevelopment in Children.” Lee, Sun, & Levy. January 2019

Speakers at the PANDA Symposium presented a “diverse body of cutting-edge work” in pediatric anesthesia neurotoxicity research. Program goals included: assessing current preclinical and clinical knowledge in pediatric anesthesia neurotoxicity research and its evolution; developing common outcome measures; and identifying future directions for research and policy.

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Developmental Neurotoxicity: An Update. Houck, Brambrink, Waspe, O’Leary, & Ko. January 2019

These authors present the latest translational and clinical findings in anesthetic induced neurotoxicity, and directions for future research. Dr. Brambrink describes the potential in connecting clinical and experimental studies to test different exposures in different contexts with the hope of finding new biomarkers. Dr. Waspe suggests applying a toxicology model for chemical risk assessment to developmental neurotoxicity as a new approach to clinical problem solving. Dr. O’Leary gives a concise update on prominent clinical observational studies since 2017, highlighting mixed data and confounding factors.

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SmartTots Outcomes Workshop 2017: Notes From a Round Table Discussion About Outcome Measures. Jackson, McCullough, Rauh, & Salorio. January 2019

The authors provide a summary of the consensus-building workshop, convened by SmartTots, at the PANDA Symposium, aimed at finding better and more consistent neurodevelopmental outcome measures in pediatric anesthesia neurotoxicity research, and more robust study designs for the future. What are appropriate outcome measures? How do we measure both short and long-term neurodevelopmental outcomes? What scales do we use? How do we time assessments? How do we integrate clinical, imaging, and genetic outcome measures? Participants addressed these and other questions.

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Using Neuroimaging to Study the Effects of Pain, Analgesia, and Anesthesia on Brain Development. Chen, Gadi, Panigrahy, & Tam. January 2019

Presentations from Drs. Ashok Panigrahy and Emily Tam were the foundation of the session, “Lessons learned: neuroimaging studies and neurodevelopmental outcomes research.” Increasingly, neuroimaging offers an intermediate phenotype for anesthetic impact; a way to study the impact of pain and anesthetics in pediatrics. Advanced multimodal MRI techniques are useful in detecting structural, metabolic, and functional changes in children who are at high risk for prolonged exposure to anesthesia. Investigators are encouraged to integrate multimodal neuroimaging approaches into preclinical and clinical studies—these modalities can validate mechanisms of anesthesia neurotoxicity.

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Reaching Parents Through an Online Community. Boat, Monteleone, Lee, & Sun. January 2019

Reflecting the session “Engaging Stakeholders to Support Research,” this overview describes Family Talkboard, an online platform developed by Cincinnati Children’s Hospital. With pop-up communities on special topics, dedicated moderators, 24-hour digital access, and gift card incentives, Family Talkboard is successful in engaging patients, families, doctors, and researchers in real-time discussions that foster quality improvement and patient-oriented outcomes research. This model presents a structured, dynamic way to engage all interested parties in discussions of anesthetic neurotoxicity.

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Engaging Stakeholders to Promote Safe Anesthesia and Sedation Care in Young Children. Jackson, Chen, & Dworkin. January 2019

The PANDA Symposium provided opportunities for roundtable discussions on important topics. The authors summarize a session that explored new ways to engage families, clinicians, researchers, and other stakeholders in issues of patient safety in pediatric anesthesia. Participants discussed the use of online portals to stimulate patient input; public-private partnerships; NIH initiatives to improve the dissemination of research results; and FDA efforts to bolster engagement following passage of a new law promoting drug development.

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Anesthesia Exposure in Children, Practitioners Respond to the 2016 FDA Drug Safety Communication. Pinyavat et al. January 2019

As a response to the 2016 FDA Drug Safety Communication, the session “Anesthesia Exposure in Children During Surgical and Non-Surgical Procedures” featured a panel of representatives from pediatrics and obstetrics. They answered questions: How are the FDA label changes affecting clinical practice vis-a-vis patient discussions, timing, and frequency of procedures? Are professional societies providing discussion guidelines? Are national meetings addressing the FDA warning and label changes? A Deputy Director from the FDA explained, and received critical feedback on, the FDA process leading up to the safety warning.

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Prolonged Anesthetic Exposure in Children and Factors Associated With Exposure Duration. Ing, Ma, Klausner, Dutton, & Li. January 2019

Investigators conduct a database review of pediatric anesthetic records (N=2,613,344). Findings show a mean anesthesia exposure of 83-107 minutes and a median of 57 minutes. Prolonged exposure = 7% in pediatric patients and 15% of infants. For the top ten procedures in infants (N =96,603), ranging in time from 22 to 712 minutes; the median is 75 minutes; and there is prolonged exposure in 20.5% of cases. Higher exposure times associate with higher ASA scores, university setting v. surgery center, and certain patient and hospital characteristics. High variability in cases makes it difficult to draw conclusions about the association of neurodevelopmental risk with longer anesthesia duration.

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Outcomes Research in Vulnerable Pediatric Populations. Lee, Diacovo, Calderon, Byrne, & Ing. January 2019

The authors describe challenges and special considerations in doing research on neonates, infants with congestive heart disease, children with low socio-economic status, and children of incarcerated parents. Neonates, as a “small market” to drug companies, are a neglected group in clinical research; >65% of their drugs are off label and there are few drug safety studies. Infants who have had open-heart surgery show higher rates of autism and higher risk for long-term problems in executive function and social cognition. Studies in children on Medicaid show increased risk for mental disorders, developmental delays, and ADHD after anesthesia. Children with incarcerated mothers are at higher risk for multiple emotional and behavioral problems.

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Epidemiology and Resource Utilization of Simple Febrile Seizure-associated Hospitalizations in the United States, 2003-2012. Huang, Li, & Sun. January 2019

In this retrospective analysis of inpatient data, the authors look at changes in hospital and resource utilization for U.S. children <6 years with simple febrile seizure (SFS), a self-resolving convulsion. Findings from 2003 to 2012 show an SFS-related decrease in these areas: 1) the weighted proportion of hospitalizations due to SFS; 2) annual rate of SFS hospitalizations per 100,000 population; 3) use of CT, EEG and lumbar puncture; 4) mean length of stay; and 5) mean hospital costs. The marked changes may be due to improved clinical adherence to American Academy of Pediatrics practice parameters.

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Early Developmental Exposure to Repetitive Long Duration of Midazolam Sedation Causes Behavioral and Synaptic Alterations in a Rodent Model of Neurodevelopment. Xu et al. January 2019

Does repeated, long-duration exposure to midazolam, as patients in intensive care settings often experience, cause lasting harm to the developing brain? Investigators say yes, the drug can alter the structure and function of the brain. Their study uses in vivo mouse hippocampal cells and an in vivo rat cortical neuron model. Findings in young adult mice with early exposure to the drug show deficits in Y maze performance and fear-conditioning tests. Subjects have a reduced rate of adult neurogenesis in the dentate gyrus brain region, a decrease in presynaptic terminals, and an increase in excitatory postsynaptic terminals.

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Summary of Preclinical Poster Presentations at the Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Symposium. Griffiths et al. January 2019

The authors present a summary of six moderated preclinical poster sessions describing two studies in c.elegans (young larvae) exposed to isoflurane; three studies in mice exposed to isoflurane; and one study in rats exposed to ketamine. The focus is defining a phenotype for AIN, understanding mechanisms of injury, and discovering potential inhibitors of neurotoxic effects. The applicability of preclinical findings to humans remains uncertain, especially in terms of timing and duration of exposure. The critical neurodevelopmental window for periods of maximal synaptogenesis varies by species.

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A Review of Clinical Poster Presentations at the Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Symposium. Haché et al. January 2019

The PANDA Symposium included four clinical poster sessions on anesthesia neurotoxicity research. Two sessions addressed the lack of standardization in clinical study design, particularly with age, type, and duration of exposure. The authors suggest future clinical trials develop more consistent study parameters, and make more use of peri- and post-operative neurocognitive testing and imaging. The third session covered pre and post-op MRI with neonates as a way to quantify neuroanatomic change. The fourth session described ways to quantify and minimize MRI exposure in children, suggesting clinicians prioritize “actionable” aspects of scans.

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Anesthesia and Neurodevelopment in Children: Many Important Questions Remain Unanswered. Sun, Lena S., MD. January 2019 (Editorial)

While tracing a more than a decade of significant progress in stakeholder meetings and research on pediatric anesthesia neurotoxicity, the author finds research funding falling short, despite a steady increase in published studies. As a result, there are still many basic questions about anesthetic neurotoxicity in children: Who are the vulnerable population cohorts? What are the specific deleterious neurodevelopmental effects? What are specific exposure conditions, including duration, frequency, and types of agents? When are the critical ages of exposure?

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2018 Archive


Look for us during 2019 at the following events:

  • SPA/AAP Pediatric Anesthesiology, March 15 – 17, 2019, Houston, TX
  • IARS Annual Meeting, May 17–20, 2019 Montreal, Quebec, Canada

  • Society for Pediatric Sedation Conference, May 20 – 22, 2019 Aurora, Colorado

Research News & Updates

Neurocognitive Impact of Anesthesia in Children. Lei, Ko, & Sun. December 2018.

Referencing 45 studies/articles published from 2005-2018, the authors review evidence of pediatric anesthetic neurotoxicity in pre-clinical to human research. This article describes 1) cellular effects of specific anesthesia agents on rodents and non-human primates; 2) clinical studies showing increased and no increased risk of adverse neurodevelopmental risk; 3) studies showing increased and no increased risk after single exposure; and 4) studies describing increased and no increased risk by age of exposure.

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Influence of Surgical Procedures and General Anesthesia on Child Development Before Primary School Entry Among Matched Sibling Pairs. O’Leary et al. November 2018

Using retrospective cohort analysis, the authors look for evidence of developmental problems following early exposure to general anesthesia of one sibling in 10,897 sibling matched pairs ages 5-6 years. Results of the Early Developmental Instrument, EDI, a test of readiness to learn in five domains, shows no difference in the adjusted odds of early developmental vulnerability or scores between the exposed and unexposed siblings. Completed EDIs, from birth on, for eligible subjects are included in the study.

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Anesthesia in the Pediatric Patient. Brockel, Polaner & Vemulakonda. November 2018

The authors discuss the evolution of pediatric anesthetic practice; risks of general anesthesia; ways to moderate exposure; how to help families make decisions about optimal timing; and anesthetic approaches to non-emergent urologic surgery. Neonates and infants, when compared to older children, are at increased risk for cardiovascular and pulmonary problems, and long-term developmental problems. Adverse findings of anesthesia-induced neurotoxicity in animal models do not currently translate to humans. Regional anesthesia may reduce anesthesia exposure and improve outcomes.

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A case report of multiple anesthesia for pediatric surgery: 80 anesthesia applications in a period of 6 years. Oba & Türk. November 2018

Investigators explore the case of a 9 year old with corrosive esophagitis having 80 anesthesia exposures in six years, including propofol, fentanyl, rocuronium, and sevoflurane. Findings show no permanent side effects due anesthesia exposure. A psychiatric consult associates minimal psychological and learning problems with frequent hospitalization.

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An Open Label Pilot Study of a Dexmedetomidine-Remifentanil-Caudal Anesthetic for Infant Lower Abdominal/Lower Extremity Surgery: The T REX Pilot Study. Szmuk et al. November 2018

A study in 60 infants, ages one to 12 months, explores the feasibility of co-administering dexmedetomidine with remifentanil and neuraxial block technique as a less toxic anesthesia regimen for surgeries of >2 hours. Findings show the combination is effective in 87.5% of infants. 45/56 infants had at least 1 episode of hypertension; 10 had mild hypotension; and 4 had moderate hypotension. Six infants needed rescue sevoflurane and one needed a dose of propofol. Four infants did not complete the protocol.

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Fundamentals of fetal toxicity relevant to sevoflurane exposures during pregnancy. Chai, Cheng, & Jiang. November 2018

What is the mechanism of fetal neurotoxicity following a mother’s exposure to sevoflurane during pregnancy and/or fetal intervention in the second trimester? Investigators associate fetal toxicity with oxidative stress (a kind of physical stress due to the imbalance between unstable molecules and protective nutrients), neuroinflammation, death of neural cells, and synaptic changes. The mechanism of toxicity may include increases in tau protein phosphorylation, associated with neurodegenerative disease, and abnormal methylation, associated with problems in the way genes turn on and off.

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A Systematic Review and Narrative Synthesis on the histological and neurobehavioral long term effects of dexmedetomidine. van Hoorn, Hoeks, Essink, Tibboel, & de Graaff. November 2018

The authors find 20/661 preclinical and 0/240 clinical studies meet the eligibility criteria for their review of dexmedetomidine, DEX. Results: 3/11 studies looking at histologic (tissue) injury implicate DEX for caspase-3 activation or apoptosis; 13/16 studies adding another anesthetic confirm the addition reduces injury; 3/7 rodent studies with neurobehavioral tests show no negative effects of DEX in animals < PN Day 21; and 6 studies show DEX, when given after another anesthetic, reduces negative side effects.

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The impact of general anesthesia on child development and school performance: a population-based study. Schneuer FJ et al. June 2018

Investigators look for evidence of developmental problems and poor school performance in 211,978 children exposed to general anesthesia at <48 months.  Sources include school-entry developmental assessments in 2009, 2012, or grade 3 school test results from 2008-2014. Findings from assessments and test scores show this cohort at 17% higher risk of being “at risk” developmentally; at 23% higher risk for low reading scores; and at 34% higher risk for low math scores.  Children with only one hospitalization have less developmental risk and better reading scores, but still have low math scores.

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CORRESPONDENCE: Can population cohort studies assess the long‐term impact of anesthesia in children? Ritchie‐McLean & Wilmshurst. October 2018.

Regarding Schneuer et al, above, the correspondents comment, “too many confounders remain to be able to draw meaningful conclusions from this study alone.” In particular, children with only a single hospital stay are included, with no comparison to a control group of children never admitted; a cohort of well children with a single, short admission would also be helpful. Secondly, children with autism may be overrepresented and, finally, gender differences require special controls, given other study results showing boys twice as likely to be classified as developmentally vulnerable.

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CORRESPONDENCE: Reply to Ritchie‐McLean, Susanna; Wilmshurst, Sally, regarding their comment “Can population cohort studies assess the long‐term impact of anesthesia in children?” Schneuer et al. December 2018.

Dr. Schneuer responds to question about confounding factors presented in the correspondence, above. “Our study has strived to address confounding factors using multiple methodological and analytical approaches.” Regarding control groups, there is no comparison group of children with hospitalizations not requiring general anesthesia due to heterogeneity issues and other serious underlying conditions with neurodegenerative effects. Secondly, children with autism and special needs are excluded from the study. Finally, there are adjustments for gender, given concerns about the relatively higher proportion of boys exposed to general anesthesia and also classified as developmentally higher‐risk.

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The Effect Of General Anesthesia On The Developing Brain: Appreciating Parent Concerns While Allaying Their Fears. Luke S. Janik, MD. October 2016.

There is widespread public fear about anesthesia in children, confounded by sensational headlines in the media. In response, the authors discuss responsibilities of anesthesia professionals in discussing the risks of general anesthesia with parents and families; they review pre-clinical evidence, observational studies, and other recent research.

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Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure. Wang et al. December 2018

Using lipodomics, the authors search for the underlying mechanism and a biomarker for anesthesia-induced neuronal damage in PN Day 5-6 monkeys exposed to sevoflurane. Analysis of nearly 20 classes and subclasses of lipids in the blood serum of these subjects reveals significant changes in serum lipids and metabolites along with short chain acylcarnitines in the brain and cerebrospinal fluid. These changes reflect an energy deficient, proinflammatory brain state.

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Electron microscopy techniques employed to explore mitochondrial defects in the developing rat brain following ketamine treatment. Eustaquio et al. December 2018

Investigators study the effect of ketamine on mitochondria in the brain cells of neonatal rats, using older/classic and newer/3 dimensional, 3D, electron microscopy techniques. Classic microscopy reveals ketamine induced mitochondrial swelling. Newer, 3D microscopy confirms mitochondrial swelling and suggests mitochondrial fission. Statistical analysis in 3D shows larger mitochondrial volume per unit surface area in treated v untreated neurons, providing ultrastructural evidence of ketamine’s proposed mechanism of neurotoxicity in the developing rat brain.

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Anesthesia affects excitatory/inhibitory synapses during the critical synaptogenic period in the hippocampus of young mice: Importance of sex as a biological variable. Ju et al. November 2018

Investigators explore the neurobiological effect of sevoflurane on the hippocampus of male v female mice at PN Day 16-17, a critical period in the development of synapses. Males show an increase in the frequency of miniature excitatory postsynaptic currents and protein/mRNA expression levels of excitatory synaptic molecules, but no increase in excitatory synapse number. Females show changes in inhibitory postsynaptic currents. Both sexes show an increase in protein/mRNA inhibitory synaptic activity.

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Early life exposure to extended general anesthesia with isoflurane and nitrous oxide reduces responsivity on a cognitive test battery in the nonhuman primate. Talpos, Chelonis, Li, Hanig, & Paule. November 2018

To explore the effects of anesthesia on learning and behavior, investigators expose PN Day 5-6 monkeys to isoflurane, followed by the NCTR Operant Test Battery, OTB. This is a series of cognitive tests, similar to those used in rats and humans to measure learning, memory, color discrimination, and motivation. Study results with the monkeys, beginning at 7 months of age, show a decrease in responses to motivation and learning task measures.

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Effects of repeated exposure to different concentrations of sevoflurane on the neonatal mouse hippocampus. Azimaraghi et al. November 2018 (Article in Portuguese)

What is the effect of repeated exposure to sevoflurane, SEVO, on the neonatal brain? To answer, scientists administer SEVO for 30 minutes/day for 7 days to 18 neonatal mice, divided into 3 groups: Group A-SEVO at 1.5%; Group B: SEVO at 3%; and Group C: inhaled oxygen only. Findings show statistically insignificant reductions in hippocampal volume in Groups A and B compared to C; ∼29% and ∼43% fewer neurons in Groups A and B, respectively, than C; and dendrite lengths shorter by ∼8% and ∼11% in Groups A and B, respectively, than C.

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Tuesday, 11/27 is Giving Tuesday and SmartTots needs your help!

Important anesthetic neurotoxicity investigations continue in both the preclinical and clinical arenas. There’s been some progress with the latest research indicating that single dose, short duration is most likely safe, but, the research and debate of this critical issue carries on as the best available data regarding repeated or prolonged exposures remain inconclusive. SmartTots is continuing its efforts to support research that would reduce the risks of anesthesia and sedation for children. Therefore, we very much need your help in these efforts. Through a very generous SmartTots benefactor, every dollar of your donation will be matched by 50 cents.

Learn how you can help at

Look for us during 2019 at the following events:

  • SPA/AAP Pediatric Anesthesiology, March 15 – 17, 2019, Houston, TX
  • IARS Annual Meeting, May 17–20, 2019 Montreal, Quebec, Canada

  • Society for Pediatric Sedation Conference, May 20 – 22, 2019 Aurora, Colorado

Research News & Updates

Neurotoxicity of Anesthesia in Children: Prevention and Treatment. Vinson AE and Houck CS. October 2018

Investigators review emerging human data on pediatric anesthesia neurotoxicity, particularly the effects on learning. The aims of future research include finding mechanisms of anesthesia-induced neuronal injury, medications to prevent injury, and therapies to enhance recovery. Until more is known, clinicians are encouraged to minimize the child’s exposure to anesthesia where possible and consider alternative immobilization techniques for non-painful surgeries, like imaging.

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Reducing the risk in pediatric anesthesia-what should we know-what should we do. Ziegler B, Becke K, and Weiss M. September 2018

The authors respond to the 2016 FDA warning, concerns about child neurodevelopment, and ongoing worldwide discussions about safety in pediatric anesthesia. Their article summarizes the state of science on anesthesia risk for children and describes opportunities to minimize them.

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Sedative and Anesthetic Neurotoxicity in Infants and Young Children: Not Just an Operating Room Concern. Pradip P. Kamat, Sapna R. Kudchadkar, and Harold K. Simon. September 2018

In their commentary, the authors caution that the 2016 FDA warning, with subsequent 2017 changes on drug labels, goes far beyond the operating room. There are clinical settings, including the PICU, the ER, outpatient clinics, and other non-operating room areas where continuous and prolonged used of general anesthesia infusions, opioids, and sedative agents are becoming a part of daily practice—where clinicians must strongly consider the FDA warning.

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Intravenous versus inhalational anesthesia for pediatric inpatient surgery – A systematic review and meta-analysis. Scheiermann P, Herzog F, Siebenhofer A, Strametz R, and Weberschock T. September 2018

Are volatile anesthetics, inhaled agents that provide general anesthesia, better than intravenous anesthetics in preventing pediatric complications, including cognitive dysfunction? Using data on 762 children in nine clinical trials, the authors find a significantly higher risk for oculocardiac reflex in strabismus surgery under propofol. There is a significantly lower risk of postoperative nausea and vomiting after general anesthesia with intravenous anesthetics when compared to volatile anesthetics, but no further differences.

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Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort. Shi et al. June 2018

What is the incidence of procedures requiring general anesthesia, GA, in children < 3 years? This retrospective review, with a cohort of 20,922 children born between 1994 and 2007, reveals 1 in 7 children have at least one exposure to GA before age 3. One in 4 children, including those with exposure > 3 hours and multiple exposures, fall into the high-risk category addressed in the 2016 FDA warning on pediatric anesthesia. Predisposing risk factors include prematurity, male sex, low birth weight, and C-section delivery.

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Estimating pediatric general anesthesia exposure: Quantifying duration and risk. Bartels et al. June 2018

What is the duration of pediatric anesthesia in contemporary practice? The authors conduct a retrospective cohort analysis using five years of data, including 1,548,021 pediatric anesthetics. Findings show the median duration is 57 minutes and 145 minutes for the 90th percentile. In children < 1 year, the median duration is 79 minutes and 210 minutes for the 90th percentile, with 13% exposed for > 3 hours. Overall, 94% of children have exposures of < 3 hours. Certain groups are at risk for longer exposure times.

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Safety of Anesthetics in Children. Adam C. Adler, Kathleen Chen, and Dean B. Andropoulos. May 2017

The 2016 FDA warning has implications for graduate medical education, particularly for trainees in procedure-based specialties and many surgical specialties. The authors question if restrictions on the length of pediatric anesthesia will diminish the time residents and fellows have to gain needed skills. Will the warning reduce the abilities of future trainees? Will the warning change the dynamics of structured apprenticeships? How do the specialties preserve the quality of resident education while maintaining patient safety?

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Fetal Surgery Decreases Anesthesia-Induced Neuroapoptosis in the Mid-Gestational Fetal Ovine Brain. Olutoye et al. October 2018

Does fetal surgery decrease anesthesia-induced brain cell death? To answer, investigators give pregnant sheep a low or high dose of isoflurane with and without surgery in the fetus, then measure fetal brain cell death at mid-gestation using anti-caspase-3 antibodies. Findings show less brain cell death in the dentate gyrus and pyramidal layer of the hippocampus with high and low dose isoflurane plus surgery. Fetal surgery does not affect the frontal cortex or endplate.

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MicroRNA-107 regulates anesthesia-induced neural injury in embryonic stem cell derived neurons. Jiang et al. October 2018

The authors use an in vitro model of rat brain embryonic stem cell-derived neurons to study the effects of microRNA-107 (miR-107), a molecule involved in gene expression, on ketamine (K) -induced neural injury. Findings show K induces brain cell death, neurite degeneration, and upregulates miR-107 in neurons. miR-107 directly and inversely regulates BDNF, a protein that supports nerve survival. Inhibition of BDNF reverses the protective effect of miR-107 down regulation. The miR-107/BDNF signaling pathway plays a key role in regulating K-induced neural injury.

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Signaling network between the dysregulated expression of microRNAs and mRNAs in propofol-induced developmental neurotoxicity in mice. Jiang et al. September 2018

How does propofol affect microRNAs (miRNAs), messenger RNAs (mRNAs), and signaling networks in the brain? To answer, investigators expose PN Day 7 mice to propofol and harvest brain cells for analysis. Findings on PN Day 7 show propofol-induced brain cell death and impaired memory function, 100 altered mRNAs, 18 dysregulated miRNAs, and 34 dysregulated miRNA-mRNA target pairs. At PN Day 60, there is abnormal expression of 49 mRNAs and 4 miRNAs. The dysregulation of miRNA-mRNA signaling may play a role in propofol-induced developmental neurotoxicity.

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Effect of melatonin on attenuating the isoflurane-induced oxidative damage is related to PKCα/Nrf2 signaling pathway in developing rats. Li et al. September 2018

Does melatonin play a neuroprotective role in response to anesthesia-induced oxidative stress? Yes, the neuroprotective effect relates to activation of the PKCα/Nrf2 signaling pathway. Investigators pretreat neonatal rats with melatonin prior to isoflurane administration. Findings show melatonin reduces isoflurane-induced nerve damage in the hippocampus; reduces the increase in reactive oxygen species and malondialdehyde levels (which can cause toxic stress); and mitigates reductions in superoxide dismutase and glutathione activity, which normally support healthy tissues.

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Neonatal exposure of ketamine inhibited the induction of hippocampal long-term potentiation without impairing the spatial memory of adult rats. Guo et al. August 2018

Using baby rats, investigators explore the effect of ketamine on spatial memory and long-term potentiation, LTP, (which supports nerve connections and learning) in the hippocampus. One-week-old rats receive either a low (25mg) or high (50mg) dose of ketamine. Water maze and electrophysiological tests at 10 weeks measure memory and LTP. Findings show low and high doses do not alter spatial memory, escape latency, swimming speed, or time spent in a quadrant, but do reduce induction of LTP.

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Dexmedetomidine attenuates the propofol-induced long-term neurotoxicity in the developing brain of rats by enhancing the PI3K/Akt signaling pathway. Xiao et al. August 2018

This study in neonatal rats finds that pretreatment with dexmedetomidine, DEX, in higher doses, where doses of 25, 50, 75 kgs are included in the study, significantly reduces the toxic effect of propofol and enhances P13K/Akt signaling, important to cell survival, in the hippocampus. Additional pretreatment with TDZD-8, a GSK3β inhibitor, supports DEX’s neuroprotective effects while LY294002, a P13K inhibitor, blocks them.

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Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats. Ju et al. August 2018

How does sevoflurane, SEVO, exposure in parents affect gene expression in their unexposed offspring? This study in neonatal rats finds female offspring less affected. Male progeny show abnormalities in behavior, spatial memory, and the expression of hippocampal and hypothalamic Kcc2, a factor implicated in psychiatric disorders and autism. Where there is SEVO exposure in the father only, the male progeny show some abnormalities and impaired expression of hypothalamic Kcc2, but normal spatial memory and no impairment in hippocampal Kcc2. There is a normal response to stress.

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N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish. Robinson B, Dumas M, Gu Q, and Kanungo J. August 2018

Using zebrafish embryos, investigators explore the neuroprotective effects of N-acetylcysteine, NAC, (an antioxidant) on ketamine-induced damage to development and monoaminergic neurons, normally involved in regulating many behaviors. Findings show NAC counteracts and/or prevents ketamine-induced reductions in heart rate and body length; reductions in areas occupied by serotonergic neurons; and reductions in tyrosine hydroxylase-immunoreactive, TH-IR, neurons in the brain and trunk.

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Early Developmental Exposure to General Anesthetic Agents in Primary Neuron Culture Disrupts Synapse Formation via Actions on the mTOR Pathway. Xu et al. July 2018

Researchers use cultured mouse neurons in an in vitro model to explore the way general anesthesia can interrupt pre- and post-synaptic marker expression in neuron development. Findings show isoflurane increases expression of phospho-S6, a marker for mTOR pathway activity and activates mTOR1/mTOR2 complex branches of the pathway. Abnormal expression is reversible with branch-specific inhibitors.

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Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death through Akt/Glycogen Synthase Kinase 3β/Mitochondrial Fission Pathway. Liu et al. July 2017

Using neonatal mice, the authors explore the role of astrocytes, an abundant cell type in the brain, in propofol-induced neuronal cell death. Astrocytes and neurons, isolated separately and in co-cultures, are exposed to propofol. Findings show propofol increases neuronal cell death, but does not influence astrocyte viability. Treating neuron cultures prior to propofol with BDNF (a protein that supports nerve cell survival), a GSK3β-kinase inhibitor, or a mitochondria fission inhibitor are neuroprotective along with high astrocyte to neuron ratios.

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Role of environmental stressors in determining the developmental outcome of neonatal anesthesia. Ju et al. July 2017

What environmental stressors contribute to developmental problems after neonatal etomidate, ETO, exposure? Investigators inject PN Day 4-6 mice with ETO followed by a single maternal separation on PN Day 10. Findings show an increase in hypothalamic NKCC1 mRNA and corticotropin-releasing hormone (CRH) mRNA on PN Days 13-17, as well as lower KCC2 mRNA levels, with greater changes in males. Pretreatment with bumetanide, an NKCC1 inhibitor, ameliorates most of these side effects. Short exposure to ETO and maternal separation associate with dysregulated stress response systems and neurobehavioral deficiencies that persist into adulthood.

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Neurodevelopmental effects of anesthesia and environmental factors. Anatoly E. Martynyuk, Jian-Jun Yang, and Jia-Qiang Zhang. February 2017

The authors find early exposure of baby rodents to sevoflurane and propofol, which enhance GABA A receptor activity, increases corticosterone levels and seizures, making subjects vulnerable to abnormal stress responses in adulthood. These include altered synaptic activity, impaired sensory motor gating function, and diminished memory. There is also an abnormal response to environmental stressors, including separation and deprivation after weaning, many months after exposure.

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Look for us during 2018 at the following events:

  • Society for Pediatric Anesthesia 32nd Annual Meeting, October 12th, 2018, San Francisco, CA
  • Society for Neuroscience in Anesthesiology and Critical Care, 46th Annual Meeting, October 11th – 12th, 2018, San Francisco, CA
  • American Society of Anesthesiologists, Anesthesiology 2018! October 13th – 17th, 2018, San Francisco, CA

Research News & Updates

Expert Available to Discuss Children and Anesthesia. American Society of Anesthesiology. August 2018

The ASA, through its journal articles, partnership with IARS/SmartTots, and officers is actively responding to the 2016 FDA warning on anesthesia in children and remains committed to advancing research of these issues. Repeated or lengthy use of general anesthesia may affect brain development in children, but the majority of research findings are from animal studies and they translate poorly to humans. ASA experts say anesthesia for one surgery lasting under 3 hours is considered safe. Dr. Linda Mason, ASA president-elect, is available to discuss ways that parents and children can prepare for surgery and anesthesia.

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Anesthesia and the developing brain: A way forward for laboratory and clinical research. Disma N et al. August 2018

International experts highlight directions for basic, translational, and clinical studies in pediatric anesthesia neurotoxicity research. They call for 1) lab research to clarify biological pathways of neurotoxicity; 2) animal research linking structural changes with long-term cognitive abnormalities; and 3) large, well-designed cohort studies. The scientific community should identify 4) populations at increased neurotoxicity risk; 5) environmental and health-risk modifiers to guide future trials; 6) mitigating strategies for adverse neurological effects; and 7) perioperative factors, other than anesthesia, in poor neurodevelopment.

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The effect of xenon-augmented sevoflurane anesthesia on intraoperative hemodynamics and early postoperative neurocognitive function in children undergoing cardiac catheterization: A randomized controlled pilot trial. Devroe S et al. August 2018

Is sevoflurane + xenon a good anesthetic option for children with congenital heart problems? Yes, it may be safe and feasible. Scientists place 40 children ages 4-12 years into two exposure groups: sevoflurane + xenon vs. sevoflurane alone. For both exposure groups, findings show the same post-op hemodynamics; no significant effects on working memory, inhibition, cognitive flexibility and motor tasks; and significant impairment in alertness at 2 hours post op with recovery at 24 hours. The sevoflurane + xenon group was associated with a decrease in intraoperative ephedrine (medication for low blood pressure) requirements.

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Pediatric neuroanesthesia. Lamsal R and Rath GP. July 2018.

The authors offer insights from pediatric anesthesia neurotoxicity research published in the last 18 months. They highlight information on unique perioperative issues in early surgery for pediatric drug-refractory epilepsy; reducing intraoperative blood loss and blood transfusions; the usefulness of tranexamic acid (medication for bleeding) in pediatric spine surgery; and intraoperative neurophysiological monitoring.

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The impact of general anesthesia on child development and school performance: a population-based study. Schneuer FJ et al. June 2018

Investigators look for evidence of developmental problems and poor school performance in 211,978 children exposed to general anesthesia at <48 months. Sources include school-entry developmental assessments in 2009, 2012, or grade 3 school test results from 2008-2014. Findings from assessments and test scores show this cohort at 17% higher risk of being “at risk” developmentally; at 23% higher risk for low reading scores; and at 34% higher risk for low math scores. Children with only one hospitalization have less developmental risk and better reading scores, but still have low math scores.

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General Anesthesia with Dexmedetomidine and Remifentanil in a Neonate During Oracotomy and Resection of a Congenital Cystic Adenomatoid Malformation. Cappuccio E, Thung AK, and Tobias JD. May-June 2018

The authors report on the successful use of dexmedetomidine and remifentanil in the surgical case of a 1-year-old neonate with a congenital malformation. This drug combination may offer a hemodynamically stable anesthetic with neuroprotective benefits and less cell death than other conventional anesthetics. Animal studies have demonstrated the potential safety of this combination, but to date there is limited data in human neonates.

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Long-duration general anesthesia influences the intelligence of school age children. Zhang Q, Peng Y, and Wang Y. December 2017

Investigators measure the effects of general anesthesia on intelligence in 209 children ages 6-12 years having orthopedic surgery. There are four groups based on duration of anesthesia: 1) control; 2) short duration <1 hour; 3) moderate 1-3 hours; and 4) long duration >3 hours. Results show a significant decrease in IQ scores for the long duration group at 1 and 3 months post op, resolving at the 1-year follow up. The variables of younger age at time of exposure, low maternal education level, and premature birth also influence the development of intelligence.

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Latent Class Analysis of Neurodevelopmental Deficit After Exposure to Anesthesia in Early Childhood. Ing et al. July 2017

A cohort study in 1444 children at 10 years of age measures language, cognition, motor function, and behavior following early surgery/anesthesia exposure. Findings yield four groups: 1) few deficits-78.6% of children; 2) language and cognitive deficits-6.6%; 3) behavioral deficits-10.5%; and 4) severe deficits-4.3%. Exposure at <3 years associates with group 2 only. This suggests a clinical phenotype for anesthesia exposure in children with language/cognition deficits rather than broad neurodevelopmental delay or behavioral deficits.

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Lipid profiling as an effective approach for identifying biomarkers/adverse events associated with pediatric anesthesia. Wang C et al. September 2018

How does anesthesia affect cellular lipids, the building blocks of all cells? The authors highlight lipidomics, the study of lipids at the molecular level, and its role in measuring blood lipid content/composition after anesthesia. They address altered brain lipids, lipid changes in cerebrospinal fluid, and how observable lipid characteristics may serve as an early biomarker for anesthesia-induced neurotoxicity.

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Cognitive Impairment and Endoplasmic Reticulum Stress Induced by Repeated Short-Term Sevoflurane Exposure in Early Life of Rats. Shen FY et al. August 2018

This study finds that repeated, short-term exposures to sevoflurane cause learning and memory deficits in newborn rats. A single exposure may be safe. Repeated exposures can impair long-term potentiation (important to learning and memory); downregulate (suppress) the expression of synaptogenic proteins, and upregulate (increase the response of) proteins involved in endoplasmic reticulum, ER, stress. TUDCA, a supplement and ER stress inhibitor, can reverse changes in levels of synaptic plasticity proteins and offer cell protection.

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Dexmedetomidine mitigates sevoflurane-induced cell cycle arrest in hippocampus. Bo LJ, Yu PX, Zhang FZ, Dong ZM. August 2018

Using highly pure hippocampal neuron cells from neonatal mice, scientists find neuroprotective qualities in dexmedetomidine, DEX, when administered with sevoflurane, sevo. DEX mitigates sevo-induced damage to the nerve cell growth cycle and inhibition of BDNF and TrkB, brain proteins that support cell survival. The addition of the receptor antagonist yohimbine (a tree bark extract with medicinal uses) partially blocks DEX neuroprotection.

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Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes. Daisy Lin, Jinyang Liu, Zihua Hu, James E. Cottrell and Ira S. Kass. July 2018

Using in vivo brain tissue from PN Day 7 mice, investigators examine the effects of sevoflurane, sevo, on MiRNAs–brain molecules involved with gene expression. Findings show sevo-induced changes in MiRNA expression when comparing the whole brain and the hippocampus, but no changes when comparing the no sevo to the sevo group. Sevo does have an immediate impact on the expression of specific MiRNAs in brain pathways associated with neuron development and synaptogenesis. These results create a bridge between 1) environmental factors that turn genes on and off; 2) the effects of neonatal sevoflurane; and 3) observable changes in behavior and outcomes.

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Long-Term Neurobehavioral Consequences of a Single Ketamine Neonatal Exposure in Rats: Effects on Cellular Viability and Glutamate Transport in Frontal Cortex and Hippocampus. Sampaio TB et al. July 2018

What are the effects of a single dose of ketamine on cells in the hippocampus and frontal cortex? In PN Day 7 rats, scientists find ketamine decreases cell viability in the hippocampus, but not the frontal cortex; there is no short or long-term damage to cellular membranes. Behaviorally, ketamine disrupts hippocampus-dependent object recognition in adulthood while improving motor coordination. Long term, ketamine induces an increase in glutamate transport uptake which may damage nerve cells.

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Comparison of neurotoxicity of dexmedetomidine as an adjuvant in brachial plexus block in rats of different age. Kang Z et al. July 2018

Does dexmedetomidine, DEX, cause neurotoxicity in neonates? These authors answer in the affirmative for high, but not moderate doses. Baby rats receive DEX alone or DEX with ropivacaine for brachial plexus block followed by testing for pro-inflammatory cytokines and activated caspase 3 on PN Days 14, 18, and beyond. Findings show high doses of DEX significantly reduce IL-6 and TNF-α levels at all ages, but these levels are similar in the controls. There are no significant differences in caspase 3 levels between the DEX and control groups save a higher reading for the DEX group on PN Day 5.

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Effect of multiple neonatal sevoflurane exposures on hippocampal apolipoprotein E levels and learning and memory abilities. Jiang J et al. April 2018

Apolipoprotein E, ApoE, is a lipoprotein in the brain that supports nerve development and synapses. Neonatal rats receive sevoflurane, sevo, on PN Days 7, 14, and 21 for two hours, followed by testing in the hippocampus on PN Days 33 and 97. Younger rats show 1) a significant decrease in left brain volume and length, and right brain length; and 2) significantly higher ApoE expression in CA1 and CA3 brain regions. Older rats show significantly lower left and maximum brain length and right brain volume. ApoE expression is region specific and may be reversible. Learning and memory decreases after sevo, but not significantly.

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Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice. Buratovic et al. January 2018

In this study, PN Day 10 mice receive a single dose of ketamine followed by ionising radiation, IR. Scientists observe the mice at 2, 4, and 5 months and analyze cortex and hippocampal tissue at 6 months. Subjects with co-exposure to ketamine and IR have problems with spontaneous behavior; significant deficits in learning and memory capacity for spatial acquisition and relearning; and significantly elevated levels of tau protein in the cerebral cortex. Overall, the neurotoxic effects of co-exposure are greater than the effects of ketamine alone.

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Influence of nitrous oxide on granule cell migration in the dentate gyrus of the neonatal rat. Saito H et al. 2018

Does anesthesia exposure increase the number of granule cells in the neonatal brain, a factor associated with neurological deficits? To answer, these scientists measure newly generated granule cells in the dentate gyrus brain region of PN Day 6 baby rats followed by 50% nitrous oxide, N20, on PN Day 7 and testing on PN Day 21. Findings show a decrease in the ratio of hilar/total granule cells on PN Day 21 when compared to PN Day 7. There is an increase in granule cells with N2O exposure >120 minutes.

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Look for us during 2018 at the following events:

  • Society for Pediatric Anesthesia 32nd Annual Meeting, October 12th, 2018, San Francisco, CA
  • Society for Neuroscience in Anesthesiology and Critical Care, 46th Annual Meeting, October 11th – 12th, 2018, San Francisco, CA
  • American Society of Anesthesiologists, Anesthesiology 2018! October 13th – 17th, 2018, San Francisco, CA

Research News & Updates

When Your Child Needs Surgery, Don’t Fear Anesthesia, Says American Society of Anesthesiologists. July 2018

In this recent press release, the American Society of Anesthesiologists (ASA) reassures parents about the safety of anesthesia. The ASA president explains to parents that the FDA based a 2016 warning primarily on studies in laboratory animals that may not translate to humans, and that many factors other than anesthesia can affect the developing brain. The ASA offers guidance to parents: do not delay surgery unnecessarily; talk to the anesthesia provider before your child’s surgery; rest assured that limited exposure to anesthesia is unlikely to have negative effects on behavior or learning. The ASA remains committed to advancing research on the safety of anesthesia for infants and children.

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Does pediatric anesthesia cause brain damage? Addressing parental and provider concerns in light of compelling animal studies and seemingly ambivalent human data. Lee JR and Loepke AW. July 2018

Examining more than 530 in vivo animal studies and 30 clinical studies, the authors look for evidence of anesthesia-induced brain abnormalities and functional impairment. The lowest abnormality levels associate with exposures of < 1 hour in both animals and humans. Adverse outcomes prevail regardless of exposure time, anesthetic technique, or age during exposure. Finding a specific human neurological phenotype remains elusive. The lack of definitive data on safe exposure durations, affects by age, and non-injurious anesthetic techniques make it difficult to justify changes in clinical anesthesia management at this time.

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The postoperative effect of sevoflurane inhalational anesthesia on cognitive function and inflammatory response of pediatric patients. Fan CH, Peng B, and Zhang FC. June 2018

In this investigation into post-operative cognitive dysfunction, POCD, 93 children are exposed to sevoflurane for varying lengths of time. Children exposed for ≥ 3 hours show a statistically significant higher amount of POCD than children exposed for <1 hour and 1-3 hours. The higher levels of POCD are associated with the recovery period and with changes in the expression of serum caspase-3, TNF-α, and IL-6, which are part of an index measuring inflammation.

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Choosing Wisely in pediatric anesthesia: An interpretation from the German Scientific Working Group of Paediatric Anaesthesia (WAKKA). Becke K et al. May 2018

Pediatric anesthesiologists from Germany present 10 recommendations for infants and children having surgical, interventional, or diagnostic procedures. Where there are robust indications: do not avoid or delay the procedures due to potential anesthetic neurotoxicity. During the induction of anesthesia: give parents the option of being present. Treat children with high perioperative risk, including preterm and term neonates, infants, and critically ill children, in institutions with expertise in and continuous clinical exposure to these types of patients.

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Spinal anesthesia for surgery longer than 60 min in infants: experience from the first 2 years of a spinal anesthesia program. Trifa M et al. May 2018

Is the short duration of spinal anesthesia, SA, an issue in choosing general anesthesia over SA? The authors explore this question in their retrospective study of 35 boys ≤ 3 years having genital, groin, or multiple site surgery under SA for an average of 71 minutes. Findings show SA is successful in 31/35 cases. One failure is associated with duration of surgery. Six boys, with successful SA, receive general anesthesia (dexmedetomidine ± fentanyl) for reasons other than duration of SA.

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Spinal anesthesia instead of general anesthesia for infants undergoing tendon Achilles lengthening. AlSuhebani M et al. May 2018

In their retrospective review, the authors address the potential for using spinal anesthesia, SA, as a sole agent vs. general anesthesia for lower extremity orthopedic procedures. They highlight favorable results for six infants having Tendon Achilles Lengthening, TAL, under SA, as well as effective protocols, dosing regimens, and potential adverse effects.

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Sedation Analgesia and Neuromuscular Blockade in Pediatric Critical Care: Overview and Current Landscape. Zuppa AF and Curley MAQ. October 2017

The authors address the use of sedation agents for critically ill babies in the PICU, highlighting the need to reduce adverse effects and find more optimal approaches. A need exists for greater knowledge of the way sedation affects immune function; on the role of genetics in drug disposition and response; and on sedation pharmacokinetics and pharmacodynamics for these vulnerable patients.

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Update on developmental anesthesia neurotoxicity. Vutskits L and Davidson A. June 2017

In their review, the authors comment on what experimental and available human studies reveal about the effects of anesthesia on children. The GAS and PANDA trials are currently the most robust human studies. They show no evidence of an association between exposures of <1-2 hours and poor neurodevelopmental outcomes. Three population-based studies find strong evidence for a small increase in risk. There is still very little data about the effect of longer exposures. The existing clinical data do not sufficiently rule out a causative association between longer exposures and poor neurodevelopmental outcomes.

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General anesthetics and cytotoxicity: possible implications for brain health. Armstrong R, Xu F, Arora A, Rasic N, and Syed NI. April 2017

This review offers perspectives on anesthesia-induced neurotoxicity in the brains of the very young and old. A clear consensus on the impact of general anesthesia on humans still eludes the scientific community. It remains difficult to study the effect of anesthesia on neuronal networks in humans and difficult to define the exact mechanisms that cause cognitive, learning and memory decline. The authors call for studies in animal models and highly controlled prospective epidemiological studies.

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Neurotoxicity of Inhalation Anesthetics in the Neonatal Rat Brain: Effects on Behavior and Neurodegeneration in the Piriform Cortex. Rachel A. O’Farrell, Andrew G. Foley, Donal J. Buggy and Helen C. Gallagher. June 2018.

Using PN Day 15 rats, investigators analyze the neurotoxic effects of a single dose of urethane, isoflurane, and sevoflurane on layer II of the brain’s piriform cortex.  Findings at 48 hours post dosing, and upon sacrifice, associate a reduction in brain cells with all of these agents.  Analysis at 96 hours reveals increasing neuronal degeneration and continued reduction in brain cells under isoflurane and urethane.  Sevoflurane and isoflurane-treated rats exhibit more activity and less suckling. Sevoflurane-exposed rats show an increase in rearing behavior.  In conclusion, volatile anesthetics are neurotoxic to the piriform cortex, but less so with sevoflurane.

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Adaptation of Microelectrode Array Technology for the Study of Anesthesia-induced Neurotoxicity in the Intact Piglet Brain. Geyer ED et al. May 2018

The authors use enzyme-based Microelectrode Array Technology, MEA, on the brains of neonatal piglets to explore mechanisms of anesthesia-induced neurotoxicity (AIN). The technology proves useful in measuring glutamate, enabling the hypothesis that AIN is caused in part by glutamate dysregulation.

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Now available! The SmartTots Panel Livestream from the 2018 IARS Annual Meeting: Neurotoxicity in Children Exposed to Anesthesia

Recording available at:

Look for us during 2018 at the following events:

  • Society for Pediatric Anesthesia 32nd Annual Meeting, October 12th, 2018, San Francisco, CA
  • Society for Neuroscience in Anesthesiology and Critical Care, 46th Annual Meeting, October 11th – 12th, 2018, San Francisco, CA
  • American Society of Anesthesiologists, Anesthesiology 2018! October 13th – 17th, 2018, San Francisco, CA

The 2018 PANDA Symposium gathered stakeholders from across the globe

Click here to read a summary of the important outcomes from the 6th biannual PANDA Symposium

Dr. Lena S. Sun shares her plans for SmartTots

Dr. Lena Sun, the new SmartTots Medical Director, shares her ideas and goals for the future of pediatric anesthesia neurotoxicity research – click here to view the video.

Research News & Updates

SmartTots Update Regarding Anesthetic Neurotoxicity in the Developing Brain. Beverly Orser, Santhanam Suresh, and Alex Evers. April 2018

The article highlights SmartTots achievements in supporting both preclinical and clinical research in pediatric anesthesia neurotoxicity. The field has advanced substantially, but key questions remain about the neurocognitive effects of anesthesia type, dose, and duration on the immature human brain. The authors call for greater coordination among investigators in different labs; more robust, reliable, and reproducible data from preclinical studies to guide the design of clinical trials; greater rigor when interpreting and extrapolating results; and the development of key research priorities.

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SmartTots: Quo Vadis? Laszlo Vutskits, MD, PhD. April 2018

Where are we going? In his editorial, the author highlights the SmartTots mission, the latest update on SmartTots-related research activities, and today’s challenges in translating preclinical to clinical pediatric neurotoxicity research. The field needs a research agenda with a roadmap that reflects consensus on key research questions. Clinical research needs to be “iterative and nuanced,” as Dr. Orser says; needs to address drug type, dosage, and number of exposures; and needs to uncover a phenotype, observable characteristics, for early anesthesia exposure. The author calls for active involvement by the entire anesthesia community to understand how neurocognitive outcome is driven by the interaction among drug exposure, surgery, and the changing patterns of homeostasis.

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Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study.  DO Warner et al. April 2018

This matched cohort study tests the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia at < 3 years are associated with adverse neurodevelopmental outcomes. Investigators administer a battery of neuropsychological assessments to a total of 997 children at ages 8-12 or 15-20 years. Findings show no association between exposure and general intelligence. Single exposure associates with no changes in neuropsychological testing domains, but parents report more problems with reading and executive function. Multiple exposures associate with a modest decrease in processing speed and fine motor skills, with no changes in other neuropsychological domains. Parents report more problems in reading, behavior, and executive function.

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The Challenges of Translation. Evan D. Kharasch, MD, PhD. April 2018

The editor voices frustration over the 2016 FDA warning about anesthesia in young children and the subsequent 2017 changes in drug labeling. In this context, he highlights two articles, from the April 2018 edition of the Journal of Anesthesiology. One is an animal study by Dr. Jevtovic-Todorovic; the other a retrospective review of human evidence by Drs. Davidson and Sun. The editor also gives three past examples of findings from in vitro and animal studies that caused alarm about drug toxicity, and in some cases FDA involvement, but were ultimately found to have no clinical relevance or were redefined in a clinically relevant way.

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Young Brain and Anesthesia: Refusal of Anesthesia Is Not an Option! DJ Culley and MJ Avram. April 2018

This article addresses the rise in concerns about anesthetic neurotoxicity in children based primarily on findings from in vitro and animal studies. The authors highlight Dr. Jevtovic-Todorovic’s review of the basic science literature leading up to the 2016 FDA warning on the use sedatives and anesthetics children and pregnant women. Investigators discuss current problems in translating preclinical findings to the clinical arena, encourage clinicians to be aware of potential risks of general anesthesia, and to participate in shared decision-making with parents.

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Anesthesia and Neurodevelopment in Children – perhaps the end of the beginning. DO Warner, Y Shi, and R Flick. April 2018

Why are the neurotoxic effects of anesthesia in children difficult to detect? Could it be there are no problems? The authors give examples of toxicity found in laboratory studies later confirmed in children. Neurocognitive injury, including deficits in higher cognitive skills and complex behaviors, may take time to appear. Population samples, using mean differences, may hide the small number of children who are highly affected. Clinical signs of neurotoxicity are not well defined; it is difficult to separate them from other factors. A conceptual framework, with a research roadmap, may help investigators find answers to these difficult questions.

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Clinical Evidence for Any Effect of Anesthesia on the Developing Brain. AJ Davidson and LS Sun. April 2018

A comprehensive review of published clinical studies assesses the long-term cognitive effects of anesthesia in children. The authors look at studies measuring academic performance/school readiness; studies providing a clinical diagnosis, like ADHD; and studies showing results of neuropsychological tests, like IQ tests. It remains difficult to say that early anesthesia exposure causes poor neurocognitive outcomes–human evidence is weak and there is a high likelihood of confounding factors. There is growing clinical evidence that a single, brief, early exposure to anesthesia is not associated with long-term deficits.

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Non-sedation of the neonate for radiologic procedures. RB Parad. March-April 2018.

The author addresses issues for radiologists who perform imaging on high-risk, pre-term and term neonates with recommendations for and guidance on non-sedated imaging. Radiologists must assess the risks of sedation to the baby, look for ways to do the imaging procedure without sedation, or find ways to reduce the dose and duration. The clinician must also weigh the relative risks of different neonatal imaging modalities. High-risk neonates have unique medical issues, unique issues with sedation, and often require specialized clinical staff to manage airways and ensure cardiovascular stability.

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Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions. Mutch WAC, El-Gabalawy RM, and Graham MR. March 2018.

Investigators discuss anesthetic neurotoxicity in postoperative delirium, POD, and postoperative cognitive dysfunction, POCD, hypothesizing that animal models are limited. Adult studies on perioperative management aimed at limiting POD may provide insights into POCD in children. POD may be a more useful proxy for POCD than neuronal dropout or the behavioral abnormalities in animal models. Future clinical trials should include comprehensive preoperative neuropsychometric and psychiatric testing; high fidelity intraoperative monitoring of physiological parameters; postoperative assessment of subthreshold; and full classification of POD.

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Systematic review of the neurocognitive outcomes used in studies of paediatric anaesthesia neurotoxicity. NG Clausen, S Kahler, and TG Hanson. February 2018

A review of 67 studies from 19 countries identifies measures used to assess long-term neurocognitive outcomes following general anesthesia in children <18 years. Most assessments look at cognition, sensory-motor development, academic achievement, or neuropsychological diagnosis. A more limited number assess outcomes like MRI, serum-biomarkers, and mortality. Inter-rater variability reflects ambiguity in rating criteria between studies and studies vary greatly in key characteristics. Future observational studies need greater consistency in essential variables, such as population, age of exposure, indications for surgery, and outcomes.

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Changes in sensory processing after anesthesia in toddlers. JM Berghmans et al. February 2018

A cohort study in boys ages 18-30 months, who were circumcised, tests pre and postoperative changes in sensory processing after pediatric anesthesia using the validated Infant/Toddler-Sensory Profile. Investigators complete assessments on 45/70 boys, revealing significant sensory processing changes in the areas of low registration, sensory sensitivity, sensation avoiding, low threshold, auditory processing, and tactile processing. Boys with pre-existing emotional and behavior problems are more vulnerable to these types of changes.

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Exposure of the Developing Brain to General Anesthesia: What is the Animal Evidence? Vesna Jevtovic-Todorovic. April 2018

In light of the FDA warning about use of anesthesia in young children, based primarily on studies in rodents, this author suggests that studies in non-human primates may provide a better foundation on which to base policy decisions. This review compares results of animal studies to those in non-human primates, who are closer to humans in brain development and may react in similar ways to anesthesia timing, dose, and complexity.

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A neurosteroid analogue with T-type calcium channel blocking properties is an effective hypnotic, but is not harmful to neonatal rat brain. N Atluri et al. February and April 2018.

In this study, PN Day 7 rat babies receive injections of hypnotic doses of ketamine or the neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH). Investigators assess hypnotic properties, therapeutic index, developmental neuroapoptosis, neuronal excitability, synaptic transmission, and cognitive abilities. Findings show 3β-OH, with a therapeutic index similar to ketamine, is a relatively safe hypnotic, does not cause brain cell death, or impair cognitive development.

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Persistent alteration in behavioural reactivity to a mild social stressor in rhesus monkeys repeatedly exposed to sevoflurane in infancy. J Raper et al. April 2018.

What is the long-term impact of early, repeated exposure to anesthesia on socio-emotional behavior? To answer, investigators give rhesus monkeys multiple doses of sevoflurane in the first 6 weeks of life. Using the human intruder test, they assess social stress at ages 1 and 2 years. Results show normal fear and hostile responses with exaggerated self-directed behaviors, a sign of stress and anxiety in non-human primates that may have long-term effects.

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Caffeine Augments Anesthesia Neurotoxicity in the Fetal Macaque Brain. KK Noguchi et al. March 2018

Is caffeine safe for the brains of infants? To answer, investigators examine the effects of caffeine on fetal macaques. In utero, the monkeys receive no drug, isoflurane alone, or isoflurane + caffeine followed by tests for brain cell death. Findings show isoflurane alone associates with a 3.3-fold increase in neuronal cell death and a 3.4-fold increase in death of oligodendrocytes. Isoflurane + caffeine associate with an 8.0-fold increase in neuronal cell death and higher blood levels than the range considered safe for human infants.

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Reproducibility of science and developmental anaesthesia neurotoxicity: a tale of two cities. L Vutskits and JW Sall. September 2017

While discussing the results of two similar studies from different labs, the authors address a current problem in basic and translational pediatric neurotoxicity research—poor reproducibility of results from study to study, lab to lab. They discuss the reasons for this, including a lack of funding and dedicated researchers, and greater interest among researchers in pursuing innovative projects over the repeat of existing studies. The result is a lack of confidence in the results of individual studies and a failure to build a foundation of reliable, high quality data to support human studies.

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Look for us during 2018 at the following events:

  • SPA-AAP Pediatric Anesthesiology 2018, March 23-25, 2018, Phoenix, AZ
  • PANDA Symposium, April 14-15, 2018, New York, NY
  • IARS 2018 Annual Meeting and International Science Symposium, April 28 – May 1, 2018, Chicago, IL

  • SmartTots Panel at the IARS Annual Meeting, Sunday, April 29, 2017, 11:30 – 1:00 PM, CST
    SmartTots: Neurotoxicity in Children Exposed to Anesthesia
  • 2018 Society for Pediatric Sedation Conference, May 20-23, 2018. Atlanta, GA

Research News & Updates

Reducing the Number of Anesthetic Exposures in the Early Years of Life: Circumcision and Myringotomy as an Example. Gonzalez et al. March 2018

The authors analyze records on circumcision and myringotomy (eardrum surgery) in boys ages 6 to 36 months, concluding that clinicians should perform these and other pediatric surgeries, where possible, at the same time. Combining surgeries will reduce healthcare costs and potential neurocognitive injury due to multiple anesthesia exposures.

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S100β in newborns after C-section with general vs. epidural anesthesia: a prospective observational study. Xu et al. March 2018

A clinical study compares the effects of general anesthesia, GA, to epidural anesthesia for C-section on newborn brain damage and other maternal/fetal parameters, including blood gas measurement, APGAR score, and maternal well-being. Findings show newborn blood S100β ratios, a measure of brain damage, lower with general anesthesia. There are no significant differences in results for the other parameters.

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Long-term neurocognitive outcomes following surgery and anaesthesia in early life. Hansen TG and Engelhardt T. February 2018

The authors present a review of current laboratory and clinical evidence on the effects of anesthetic agents on neurological outcomes. Animal and laboratory data have no clear cut-off age for morphological changes and neurocognitive impairment. To date, exposures of short duration in clinical trials indicate no long-term effects on neurological outcomes. In humans, the factors of disease processes, surgical intervention, trauma, and other perioperative issues are more significant than choice of anesthetic agent.

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Emulsified isoflurane induces release of cytochrome C in human neuroblastoma SHSY-5Y cells via JNK (c-Jun N-terminal kinases) signaling pathway. Yang et al. January-February 2018

How safe is emulsified isoflurane, Elso, a potential alternative to inhalation isoflurane, and how does it damage brain cells? To answer, scientists expose cultured human neuroblastoma (brain cancer) cells to Elso. Findings suggest EIso damages by activating a critical brain-signaling pathway, the JNK pathway, and stimulating the release of cytochrome C, a brain protein. The JNK inhibitor, SP600125 shows effectiveness in protecting neural cells from EIso-induced injury.

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A Systematic Review of Risk Factors Associated With Cognitive Impairment After Pediatric Critical Illness. Kachmar AG, Irving SY, Connolly CA, and Curley MAQ. January 2018

What are risk factors for cognitive impairment after pediatric critical illness? The authors describe results of 12 studies involving neuropsychologic tests with at least one cognitive functioning dimension delivered as part of PICU follow up to children 3-18 years of age. Findings associate these risk factors with cognitive impairment: younger age at critical illness and/or older age at follow-up; low socioeconomic status; high oxygen requirements; use of mechanical ventilation; sedation and pain medications.

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Reducing sedation for pediatric body MRI using accelerated and abbreviated imaging protocols. Ahmad R, Hu HH, and Krishnamurthy R. January 2018.

This review addresses concerns about general anesthesia/sedation exposure for children needing MRIs. From a technical and clinical perspective, the authors describe innovative ways to obtain high quality images by accelerating scans, utilizing the concept of timesaving reporting elements for a given clinical indication, and abbreviating imaging protocols.

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Changes in tissue and cerebral oxygenation following spinal anesthesia in infants: a prospective study. Froyshteter et al. January 2018

Near-infrared spectroscopy, NIRS, is an imaging technique that uses light absorption to measure cell and brain activity. In this study, the authors use NIRS and linear regression to calculate changes in cerebral and tissue oxygenation (oxygen supply/levels) following spinal anesthesia. Results yield no clinically significant changes in oxygenation following administration of spinal anesthesia.

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Food and Drug Administration warning on anesthesia and brain development: implications for obstetric and fetal surgery. Olutoye OA, Baker BW, Belfort MA, and Olutoye OO. January 2018

How does the 2016 FDA warning about use of anesthesia in children and pregnant women impact anesthetic and surgical management of obstetric patients? The authors raise concerns about the use of anesthesia for C-sections; discuss fetal exposure to anesthesia during non-obstetric and fetal surgery in the second and third trimesters; and present clinical strategies for avoiding long-term neurological problems in the baby.

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Effects of short-term exposure to sevoflurane on the survival, proliferation, apoptosis, and differentiation of neural precursor cells derived from human embryonic stem cells. Park et al. December 2017

Scientists expose neural precursor cells derived from human embryonic stem cells for 2 hours to 3%, 6%, and 8% sevoflurane, followed by testing on post-treatment days 1, 3, 5, and 7. Some early negative effects of sevoflurane exposure normalize by day 7. There are no other long-term changes to cell viability, proliferation, death, and differentiation.

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Epidemiology of Exposure to Anesthesia, Surgery, and Mortality in a Children’s Hospital Population. Hoffman et al. October 2017

The authors analyze health outcomes in 104,237 cases of anesthesia exposure in 61,088 children by age, American Society of Anesthesiologists Physical Status (ASA-PS) score, individual and cumulative anesthesia duration, number of cases, and mortality risk. Findings show mortality odds ratios high for >3 cases per child (19.l) and ASA-PS >3 (16.2); lower for cumulative anesthesia duration >3 hours (9.96); and very low for individual anesthesia duration >3 hours (2.09) and <3 years of age (1.80).

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Lipoic acid inhibited desflurane-induced hippocampal neuronal apoptosis through Caspase3 and NF-KappaB dependent pathway. Zhao H, Bu M, Li B, and Zhang Y. February 2018

Can α-lipoic acid, an antioxidant found in many foods, mitigate the brain cell toxicity and death associated with desflurane exposure? Yes, according to this animal study using brain cell cultures. The helpful effect of α-lipoic acid correlates with cell survival, including inhibition of the Caspase-3-dependent pathway (involved with cell death) and activation of the NF-kappaB pathway (involved with immune function).

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Propofol Exposure in Early Life Induced Developmental Impairments in the Mouse Cerebellum. Xiao et al. November 2017

Scientists evaluate neonatal mice receiving 30 or 60 mg of Propofol for glial cell growth, dendrite development, and neuron migration—all of which support healthy brains. Findings associate Propofol with defects in the cerebellum, including reductions in Purkinje neuron cells, their dendrite length, and impairments in Bergmann glia development. There is a delay in granule neuron migration between brain layers in mice receiving the higher dose of Propofol, but not the lower.

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Effect of repeated neonatal sevoflurane exposure on the learning, memory and synaptic plasticity at juvenile and adult age. Liang et al. November 2017

The authors explore the effect of early exposure to sevoflurane on long-term learning and memory.  Baby rats receive 2 hours of sevoflurane on PN Days 7, 14, and 21 followed by tests for spatial memory and synaptic plasticity.  Sevoflurane exposure does not result in marked behavioral abnormalities. There is significant inhibition of long-term potentiation (strength of nerve connections) in the hippocampus, with augmentation of the paired-pulse facilitation ratio–noticeable effects in adolescence which tend to lessen in adulthood.

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Repeated 2% sevoflurane administration in 7‑ and 60-day-old rats: Neurotoxicity and neurocognitive dysfunction. Huang et al. November 2017

A study in rats explores the effect of 2% sevoflurane for 1 h on brain cell death and neurocognitive dysfunction. Tests show neither brain cell death nor spatial memory impairment for rats receiving sevoflurane on PN Day 7 only or PN Day 60 only. There is a significant increase in brain cell death and poor performance on spatial memory tests for rats receiving sevoflurane on PN Days 7 and 60.

Read More

SmartTots now accepts recurring donations! Discover the effortless satisfaction of a monthly contribution to support our important research.


2017 Archive


The IARS announces a new SmartTots Medical Director!

The IARS recently announced the appointment of Lena S. Sun, MD, as the Medical Director of SmartTots. Dr. Sun is an established basic science, translational and clinical researcher, a board-certified physician in Pediatrics, Anesthesiology and Pediatric Anesthesiology and a practicing pediatric anesthesiologist. As the Medical Director of SmartTots, she will help promote and advocate for research to advance and ensure safety of anesthesia in children.

She will specifically work with researchers, clinicians, parents and other relevant stakeholders to develop future research strategies to address the pressing challenges to understand the effects of anesthetic and sedative agents in the developing brain. She will also work with all stakeholders to support the implementation and dissemination of research results related to all SmartTots-related issues.

There’s still time to apply!

Look for us during 2018 at the following events:

  • ·         SPA-AAP Pediatric Anesthesiology 2018, March 23-25, 2018, Phoenix, AZ
  • ·         IARS 2018 Annual Meeting and International Science Symposium, April 28 – May 1, 2018, Chicago, IL
  • ·         SmartTots Panel at the IARS Annual Meeting, Sunday, April 29, 2017, 11:30 – 1:00 PM, CST

Special thank you to ASA, SPA, AAP & SNACC for their generous support at their 2017 conferences!

SmartTots would like to extend a special thank you to the American Society of Anesthesiologists, the Society for Pediatric Anesthesia, the American Academy of Pediatrics and the Society for Neuroscience in Anesthesia and Critical Care for providing SmartTots with complimentary booth space at their annual meetings. We are very grateful for the ongoing support from affiliated organizations and their members.

Research News & Updates

An International, Multicenter, Observational Study of Cerebral Oxygenation during Infant and Neonatal Anesthesia. Olbrecht et al. January 2018

A multicenter study, with 453 infants <6 months having general anesthesia for 30 minutes or more, examines the association of long-term neurocognitive problems to cerebral oxygenation (oxygen in brain cells). Researchers measure degrees of oxygenation, arterial pressure, and oximetry saturation (a non-invasive test of oxygen, a ratio). Severe low oxygen saturation associates with mild and moderate cerebral desaturation (stress to the brain’s oxygen supply). ASA physical status III and IV (severe and life-threatening disease states) associate with moderate cerebral desaturation. Severe desaturation does not explain long-term neurocognitive problems.

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Predictors of Anesthetic Duration in Common Pediatric General Surgical Procedures. Anna J Klausner, Xiaoyue Ma, Guohua Li and Caleb Ing. December 2017

Using 139,879 records from the National Anesthesia Clinical Outcomes Registry, researchers identify predictors of increased pediatric anesthesia duration: ASA physical status III and IV (severe and life-threatening disease states); patient ages of <1 year and between 1 and 3 years; procedures at university hospitals v. surgical centers; and anti-reflux and bladder ureter reconstructions. Findings may indicate patients at higher risk for anesthesia neurotoxicity.

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Challenges in the anesthetic management of ambulatory patients in the MRI suites. Deen J, Vandevivere Y, and Van de Putte P. December 2017

A literature review addresses the latest findings on use of MRI in infants and children, highlighting patient safety, sedation guidelines, airway management, specific drugs, and non-drug alternatives. The authors discuss the use dexmedetomidine, chloral hydrate, and propofol; alternative non-drug techniques to induce natural sleep; protections from high noise levels, and safeguards against hypothermia in infants.

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Xenon as an adjuvant to sevoflurane anesthesia in children younger than 4 years of age, undergoing interventional or diagnostic cardiac catheterization: A randomized controlled clinical trial. Devroe et al. December 2017

A clinical trial of infants at 12 months undergoing cardiac catheterization examines the effects of sevoflurane plus xenon v. sevoflurane alone on hemodynamic stability (heart rate, arterial blood pressure, and use of vasopressors, which help increase blood pressure). Findings show no difference in measures of hemodynamic stability between cohorts. The addition of xenon does reduce vasopressor requirements, improve cell oxygen, and promote faster recovery.

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Pediatric Anesthesia Considerations for Interventional Radiology. Nelson O and Bailey PD Jr. December 2017

A discussion of children’s unique patient safety and risk assessment needs in diagnostic and invasive interventional radiology procedures. The authors highlight risk factors, including the effects of medications and contrast media; procedure specific risks; and exposure to ionizing radiation. They focus on the special periprocedural planning needs of pediatric cancer patients and children having sclerotherapy for vascular masses.

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Ionizing radiation from computed tomography versus anesthesia for magnetic resonance imaging in infants and children: patient safety considerations. Callahan et al. November 2017

This review compares and contrasts the potential risks of computed tomography, CT, without anesthesia v. MRI with anesthesia in the pediatric population. The authors discuss the implications for exam selection with examples in neuroblastoma surveillance imaging. They address advances in CT technology that allow for faster imaging, lower radiation exposure, and less need for anesthesia.

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More than 3 hours and less than 3 years: Safety of anaesthetic procedures in infants less than 3 years old subjected to surgery for more the 3 hours. Álvarez et al. October 2017

Responding to the FDA alert of December 2016, four Spanish medical societies have formed a working group to address the safety of general anesthesia and sedation in young children. Given the lack of clinical evidence to the contrary, they say general anesthesia and deep sedation are safe –but many ethical, legal, and clinical questions remain. The authors urge caution in the use of anesthesia/sedation in patients < 3 years of age undergoing surgeries of > 3 hours and prolonged sedation in the NICU.

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Perinatal and neonatal use of sedation and analgesia. McPherson C and Inder T. October 2017

What are the risks and benefits of pharmacologic anesthesia and analgesia to the fetus and neonate? How neurotoxic are these agents to the baby brain? The authors describes the clarity, controversy, and uncertainty in current research, from experimental to clinical. They discuss general anesthesia for non-obstetric surgery and C-section in the absence of regional anesthesia; the use of opioid analgesia for pre-term infants having major procedures; and the use of opioids for agitation resulting from mechanical ventilation.

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Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor κ-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats. Shi Y, Wang G, Li J, and Yu W. December 2017

A study in newborn rats tests the neuroprotective potential of administering hydrogen gas following sevoflurane v. sevoflurane alone. Results show spatial memory recognition and fear memory lower with sevoflurane alone. The addition of hydrogen gas improves cognitive function while inhibiting nuclear factor B cell (NF-κB) activation and cytokine release—both are associated with inflammation and sevoflurane-induced neurotoxicity.

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Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Ding ML, Ma H, Man YG, and Lv HY. December 2017

The authors assess the ability of EGCG, a nutrient in green tea with antioxidant qualities, to reduce sevoflurane-induced neurotoxicity. Neonatal rats receive varying doses of EGCG on PN Days 3-21 and sevoflurane on PN Day 7. Findings show EGCG improves learning and memory by inhibiting and/or mitigating sevoflurane-induced damage to, and supporting, critical brain pathways that enable nerve signals and communication from one brain region to another.

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Exposure of Developing Brain to General Anesthesia: What Is the Animal Evidence? Jevtovic-Todorovic V. December 2017

In response to concerns presented in the FDA safety warning on general anesthesia in children <3 years, and in light of limited human studies, the authors compare findings on anesthesia neurotoxicity in published studies using nonhuman primates (monkeys) and rodents (rats) as subjects.

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Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia. Yang et al. November 2017

A study in newborn rats examines the contribution of stressful life events following general anesthesia to neurodevelopmental problems. The authors inject PN Day 6 rats with sevoflurane and separate a test group from their mothers for 3 hours on PN Day 10. As adults, the test group, when compared to the group receiving sevoflurane alone, shows greater escape latencies and more problems during water maze exercises. In conclusion, post-sevoflurane stressors may contribute to long-term developmental abnormalities.

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Isoflurane exposure regulates the cell viability and BDNF expression of astrocytes via upregulation of TREK‑1. Zhou et al. November 2017

What role do astrocytes, star-like cells that connect nerve cells to blood vessels, play in disrupting cognitive functions, like learning and memory? To answer, the authors manipulate and measure TREK‑1 (a channel within neurons) within astrocytes during isoflurane exposure. Overexpression of TREK‑1 alters, while knockdown of TREK-1 inhibits, BDNF (a gene that supports nerve growth), Bax (a gene involved in cell death) and caspase‑3 (a brain protein) expression. Isoflurane‑induced cell damage in astrocytes may link to TREK‑1‑mediated inhibition of BDNF.

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Caffeine combined with sedative/anesthetic drugs triggers widespread neuroapoptosis in a mouse model of prematurity. Cabrera et al. November 2017

Researchers give PN Day 3 mice caffeine (CAF) before death and prior to administering sedative/anesthetic drugs (SADs), including midazolam, ketamine, and fentanyl. Findings show CAF, when co-administered with these drugs, significantly increases the activation of caspase 3-positive cells (brain proteins), and proves to be a “supra-additive” factor in neurotoxicity and widespread brain cell death.

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Non-Anaesthetic Effects of Volatile Anaesthetics: A Short Trip on the Sea of Translational Medicine. Krzych LJ, Szczepanska AJ. October 2017

What are the effects of non-anesthetic properties in volatile anesthetics on the brain? To answer, the authors conduct a review of recent scientific findings on the non-anesthetic effects of inhaled halogenic ethers (a compound of non-metallic elements, like iodine) on cells and tissues.

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SmartTots now accepts recurring donations! Discover the effortless satisfaction of a monthly contribution to support our important research.




September/October 2017 Newsletter

Tuesday, 11/28 is Giving Tuesday and SmartTots needs your help!

As you read through this newsletter and catch up on the latest scientific research, you will be reminded that important anesthetic neurotoxicity investigations continue in both the preclinical and clinical arenas. The research and debate of this critical issue carries on simply because the best available data remain inconclusive. SmartTots continues to accelerate its efforts to fund research to identify and lessen the risks for children. However, we need your help. And thanks to a very generous SmartTots benefactor, every dollar that you donate today will be matched by 50 cents.

Learn how you can help at

SmartTots exhibits at the 2017 JSCA Annual Meeting in Tokyo, Japan!

IARS Meetings and Education Director, Meghan Whitbeck, traveled to Japan to represent SmartTots at the 37th Annual Meeting of the Japan Society of Clinical Anesthesia (JSCA). This is one of the biggest annual meetings for anesthesiologists in Japan with over 1,000 members attending each year. The theme this year was “Knights for Safety and Quality” and distinguished speakers shared the latest knowledge in all subspecialties of anesthesiology.  SmartTots is tremendously grateful to the JSCA as they have been a generous, long-term supporter, donating nearly $40,000 since the inception of our research initiative.

Look for us during 2018 at the following events:

·         SPA-AAP Pediatric Anesthesiology 2018, October March 23-25, 2018, Phoenix, AZ

Research News & Updates

Sevoflurane Affects Oxidative Stress and Alters Apoptosis Status in Children and Cultured Neural Stem Cells. Zhou et al. October 2017

In this study, 24 children ages 12-36 months receive sevoflurane and 23 receive propofol for hypospadias repair surgery (repair of a congenital problem with the urethra and penis). Using blood samples and serum, researchers find sevoflurane exposure causes significantly higher antioxidant defense (cell activity to fight cell stress and damage), cell death, and damage to neural stem cells than propofol.

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Perioperative Hypotension in Infants: Insights From the GAS Study.
Laszlo Vutskits and Justin Skowno. September 2017

Poor definition of perioperative hypotension (low blood pressure) makes it difficult to define its risk due to early exposure to general anesthesia v regional anesthesia, and the associated risks of long-term neurobehavioral problems. The authors discuss ways in which the GAS Study, as a large prospective clinical trial, provides detailed inter-operative records and how they will help scientists resolve these uncertainties.

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Duration of general anaesthetic exposure in early childhood and long-term language and cognitive ability. Ing et al. September 2017

The authors analyze differences in language and cognitive test scores among 10-year-olds with and without early exposure to volatile anesthetics (VA). Findings show no differences in test scores with VA exposure of ≤35 minutes, but significantly lower total and expressive language scores with exposures of >35 minutes.

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What do recent human studies tell us about the association between anaesthesia in young children and neurodevelopmental outcomes? JD O’Leary and DO Warner. September 2017

This review highlights the results of five clinical studies since 2015 on anesthesia neurotoxicity in children. The authors help to integrate new findings into the available body of preclinical/clinical science, with insights and implications for clinical practice.

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Clinical update regarding general anesthesia-associated neurotoxicity in infants and children. MR Graham. September 2017

Scientists review recent, robust clinical studies on anesthesia neurotoxicity and conclude that the recent FDA warning about anesthesia may be overstated for healthy children. Other factors–prematurity, congenital and neurological abnormalities, social and environmental issues–may play a greater role in adverse neurodevelopmental outcomes.

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Anesthesia Exposure and Neurotoxicity in Children—Understanding the FDA Warning and Implications for the Otolaryngologist. Lyndsey A. Grover, Ron B. Mitchell, and Peter Szmuk. September 2017.

The 2016 FDA warning on the use of anesthesia in young children and pregnant women will result in label changes for 11 common general anesthetics and sedative agents, and all anesthetic gases. In their opinion paper, the authors discuss the implications for otolaryngology practice, suggest changes to the informed consent process, and provide data for clinicians to use when counseling families.

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Thinking, fast and slow: highlights from the 2016 BJA seminar on anaesthetic neurotoxicity and neuroplasticity. SG Soriano, L Vutskits, V Jevtovic-Todorovic, HC Hemmings, and the 2016 BJA Neurotoxicity and Neuroplasticity Study Group. September 2017

Members of the 2016 BJA Neurotoxicity and Neuroplasticity Study Group provide this comprehensive overview of evidence on the impact of anesthesia on the developing central nervous system, highlighting ongoing pre-clinical and clinical investigations. While many say the recent FDA warning is too severe, the authors call for more clinical studies to provide definitive conclusions about anesthetic neurotoxicity in humans with clinically based recommendations to guide practice.

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Age at Exposure to Surgery and Anesthesia in Children and Association with Mental Disorder Diagnosis. Ing et al. August 2017

Researchers conduct an observational cohort study using Medicaid data on 38,493 children with a single exposure to anesthesia for select surgeries and 192,465 children with no exposure in 11 age categories between 28 days and 5 years of age. Hazard analysis reveals an increased risk for a mental health disorder diagnosis across all ages of exposure with little variance in risk by timing of exposure.

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Association of prenatal exposure to benzodiazepines and child internalizing problems: A sibling-controlled cohort study. Brandlistuen et al. July 2017

A sibling/cohort study in 71,996 children associates long-term prenatal exposure to benzodiazepines (BZDs) and z-hypnotics (sleeping pills) with increased internalizing behavior (depression, social withdrawal, sadness) in the children at 1.5 years. Exposure to BZD-anxiolytics (anti-anxiety medications) associates with internalizing problems at both 1.5 and 3 years. Exposure to z-hypnotics does not associate with adverse outcomes.

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Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice. Lu et al. October 2017.

Six-day-old mice receive 3% sevoflurane 2 hours/day for 3 days. How does this affect the supportive nature of postsynaptic density protein 95 (P95) levels in the brain and cognitive function? Sevoflurane degrades P95 in the ubiquitination-proteasome pathway (important to cell growth), as well as protein levels in neurons, synaptosomes (which support nerve connections), and the hippocampus. MG 132 and Nutlin-3 inhibitors (which fight cell damage and death) reduce sevoflurane-induced cognitive impairment.

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Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain. Noguchi et al. September 2017

In this animal study, 6-day-old monkeys receive isoflurane for 3 hours. Using immunolabeling (a staining technique) and stereology (a method of quantifying biological features of tissue), researchers find brain cell death is 4 times greater in monkeys exposed to isoflurane than in the control group. Cell death in oligodendrocytes (which support healthy neuronal development) occurs throughout the brain’s white matter. Neuroapoptosis (death of neurons) occurs primarily in the cortex. Three hours of isoflurane exposure is deemed highly neurotoxic to the primate brain.

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Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats. Perez-Zoghbi JF, Zhu W, Grafe MR, and Brambrink AM. September 2017

Using baby rats, scientists explore the neuroprotective potential of dexmedetomidine (DEX) when co-administered with sevoflurane. Findings show sevoflurane and DEX at 1 µg kg -1 significantly reduce cell death in all brain regions, particularly the thalamus. Sevoflurane plus DEX at 5-25 µg kg -1 leads to increased mortality.

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Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor κ-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats. Shi Y, Wang G, Li J, and Yu W. September 2017.<

Can molecular hydrogen (H2), an odorless gas, reduce sevoflurane-induced neurotoxicity? Yes, based on this animal study. H2, when administered with or following sevoflurane, improves cognitive function and protects against sevoflurane-induced neurotoxicity by inhibiting NF-κB (proteins active in many diseases) and proinflammatory cytokine (proteins active in cell to cell signaling) release.

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Alternative technique or mitigating strategy for sevoflurane-induced neurodegeneration: a randomized controlled dose-escalation study of dexmedetomidine in neonatal rats. Lee et al. September 2017

Does Dexmedetomidine (DEX) mitigate sevoflurane-induced (SEVO) neuronal damage and brain cell death? No, based on this study in which neonatal rats receive SEVO and DEX alone and in combination. SEVO causes neuronal injury and increases cell death in all brain regions. DEX, even at highest doses, does not cause similar injury, but does not provide as much sedation and pain control as SEVO. The combination of 2.5% SEVO with > 1 µg kg -1 DEX can be fatal.

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Neurotoxicity of propofol on rat hypoglossal motoneurons in vitro. Monni L, Ghezzi F, Corsini S, and Nistri A. August 2017.

This in vitro study examines the mechanisms of propofol-induced neurotoxicity in neonatal rat hypoglossal neurons (HMs) which control tongue muscles and airway function. Findings show propofol depresses NMDA receptor-mediated responses (involved in learning and memory) and may activate GABA and glycine transmitters (which control impulses between nerves in the brain) leading to cytoplasmic (cell-related) overload and cell death.

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Potential neurotoxicity of prenatal exposure to sevoflurane on offspring: Metabolomics investigation on neurodevelopment and underlying mechanism. Jiang et al. August 2017

Researchers use metabolomics (cell function) analysis in 7-day-old baby rats to identify the neurotoxic effects of in utero exposure to sevoflurane. Analysis yields 29 metabolites (molecules) as neurotoxicity biomarkers (measurable indicators) with significant reduction in S-Adenosylmethioninamine levels, abnormal methylation, and disturbed proline metabolism–factors affecting healthy cell function and gene expression.

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Single and multiple sevoflurane exposures during pregnancy and offspring behavior in mice. Soomin Lee et al. May 2017

In this animal study, pregnant mice in their second trimester (gestational days 14-16) receive single doses of oxygen for 1 day or combinations of oxygen and sevoflurane for 1 to 3 days. Findings suggest these exposures cause neither long-lasting behavioral consequences nor changes in long-term synaptic plasticity in male offspring at 2-4 months.

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Sevoflurane Exposure during the Critical Period Affects Synaptic Transmission and Mitochondrial Respiration but Not Long-term Behavior in Mice. Woosuk Chung, Min Jeong Ryu, and Jun Young. February 2017

A study in postnatal mice examines the effect of sevoflurane on spinogenesis (formation of healthy nerve connections) and mitochondrial (cell energy) activity in the brain. Findings show sevoflurane creates an imbalance of excitatory and inhibitory synaptic transmissions and induces mitochondrial hyperactivity. No long-term behavioral problems due to anesthesia exposure are present.

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July/August 2017 Newsletter

Look for us during 2017 at the following events:

·         Society for Pediatric Anesthesia 31st Annual Meeting, October 20th, 2017, Boston, MA

·         Society for Neuroscience in Anesthesiology and Critical Care, 45th Annual Meeting, October 19th – 20th, 2017, Boston, MA

·         American Society of Anesthesiologists, Anesthesiology 2017!, October 21st – 25th, 2017, Boston, MA

Other events:

·         Paediatric Anaesthesia, Surgery and Long Term Cognitive Outcome.
Neurotoxicity and Neuroprotection: Two Faces of the Same Coin?
September 23, 2017, London, England

Join SmartTots and Rally for Medical Research!

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Research News & Updates

Debate Over Neurotoxicity in Pediatric Anesthesia Draws No Firm Conclusions.  Ajai Raj September 2017

Four pediatric anesthesiologists weigh in on why studies to date in children fail to prove that multiple and/or longer exposures to anesthesia lead to long-term cognitive problems.  Current research is highly inconsistent in addressing 1) neurotoxicity outcome measures; 2) co-morbidities; 3) minimum anesthesia dosages; 4) underlying pathologies and genetic issues; and 5) the separation of neurotoxicity from case management.

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Editorial Views: Can We Really Suggest that Anesthesia Might Cause Attention-deficit/Hyperactivity Disorder? Daryl Efron, Laszlo Vutskits, and Andrew J. Davidson. August 2017

The authors say it is a big leap to conclude that early exposure to anesthesia causes ADHD/learning disabilities. The evidence remains weak despite three human cohort studies from the Mayo Clinic Group finding this association. To determine causality, scientists must be able to 1) replicate findings in different human populations; 2) rule out confounding factors (medical, neurologic, and developmental); and 3) contest biologic plausibility (pathogenic and genetic causes of ADHD).

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Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort. Danqing Hu, Randall Flick, Michael Zaccariello, Robert Colligan, Slavica Katusic, Darrell Schroeder, Andrew Hanson, Shonie Buenvenida, Stephen Gleich, Robert Wilder, Juraj Sprung, and David Warner. August 2017

A retrospective study looks for long-term effects of multiple v. single exposure to general anesthesia in children < 3 years. Findings associate a higher frequency of learning disabilities and hyperactivity, lower cognitive ability and academic performance, with multiple exposures. Single exposure associates with some decrease in reading and language performance, but no negative effects on cognitive ability.

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Are Anesthesia and Surgery during Infancy Associated with Decreased White Matter Integrity and Volume During Childhood? Block et al. August 2017

Using MRI, researchers study the brains of 17 children, ages 12.3-15.2 years, exposed to general anesthesia for surgery in infancy.  When compared to the control group, the exposed children show lower levels of brain white matter overall as a percentage of total intracranial volume, including significantly lower volumes in several brain regions analyzed separately and decreased integrity in several white matter pathways that support brain connections and messaging.

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Effect of General Anesthesia on Neurodevelopmental Abnormalities in Children Undergoing Treatment of Vascular Anomalies With Laser Surgery: A Retrospective Review. Terushkin V, Brauer J, Bernstein L, and Geronemus R. April 2017

The authors retrospectively review charts, and conduct phone interviews with parents, of 33 children averaging 7.8 years with multiple exposures to general anesthesia (nitrous oxide, isoflurane, propofol) at < 4 years. Findings show no increase in the prevalence of neurodevelopmental disorders in these children when compared to the US population at large.

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Overexpression cdc42 attenuates isoflurane-induced neurotoxicity in developmental brain of rats. Fang X, Li S, Han Q, Zhao Y, Gao J, and Yan J, Luo A. August 2017

This study looks for the mechanism underlying isoflurane-induced neurotoxicity and associated neurocognitive impairment in baby rats. The authors conclude that isoflurane suppresses elements in brain pathways important to synaptic and neuronal growth, particularly in the cdc42, a protein-coding gene. Overexpression of cdc42 may counter the negative effects of isoflurane and help preserve spatial memory.

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Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats. Milanovic D, Pesic V, Loncarevic-Vasiljkovic N, Avramovic V, Tesic V, Jevtovic-Todorovic V, Kanazir S, and Ruzdijic S. August 2017

Scientists study the effect of propofol on brain proteins in rats, given variable doses on PN Day 7, then put to sleep at 0, 4, 16, and 24 hours after exposure. Findings show propofol is toxic to the developing brain; it interferes with synaptic dynamics; alters protein expression within the cortex and thalamus; decreases protein numbers; makes critical proteins overly sensitive; and can lead to long-term functional problems.

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Protective effects of green tea polyphenol, epigallocatechin-3-gallate against sevoflurane-induced neuronal apoptosis involves regulation of CREB -BDNF-Trk-B and PI3K/Akt/mTOR signalling pathways in neonatal mice. Ding ML, Ma H, Man YG, and Lv YH. July 2017

Can EGCG, a green tea extract with antioxidant qualities, protect the baby rat brain from sevoflurane-induced neurotoxicity? Yes, according to a study in which rats receive EGCG from PN Day 3 to 21 along with sevoflurane on PN Day 7. Results show that EGCG significantly inhibits sevoflurane-induced brain cell death and neurodegeneration while protecting brain pathways and signaling. Water maze tests show improvements in learning and memory.

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Use of a Piglet Model for the Study of Anesthetic-induced Developmental Neurotoxicity (AIDN): A Translational Neuroscience Approach. Whitaker EE, Zheng CZ, Bissonnette B, Miller AD, Koppert TL, Tobias JD, Pierson CR, and Christofi FL. June 2017

The article praises the neonatal piglet as an ideal model for pre-clinical study of human neurodevelopment, including the effects of anesthesia on brain cell death. The authors provide guidance to researchers on how to work with piglets whose anatomy and physiology enable the study of many human perioperative conditions.

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Ketamine-induced apoptosis in the mouse cerebral cortex follows similar characteristic of physiological apoptosis and can be regulated by neuronal activity. Wang Q, Shen FY, Zou R, Zheng JJ, Yu X, and Wang YW. June 2017

A study in baby mice compares ketamine-induced brain cell death with more naturally occurring brain cell death. Findings show similarities in brain cell targets, particularly in the cell layers, cell patterns, and cell-types. Both types of cell death destroy cells in the cerebral cortex, including GABAergic neurons, which make up 10-20% of all neurons. Increasing neuronal activity naturally may be a way to reduce the adverse effects of general anesthesia.

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Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and Cognition in Developing Rats. Wu J, Hao S, Sun XR, Zhang H, Li H, Zhao H, Ji MH, Yang JJ, and Li K. April 2017

Scientists pretreat baby rats with elamipretide, a drug candidate, used to treat cell dysfunction in a number of diseases, followed by 1.5% isoflurane for 6 hours on PN Day 7. Early assays and tests on PN Days 21, 40, and 60 show elamipretide protects against brain cell stress, cell damage, and cognitive deficits associated with anesthesia-induced neurotoxicity. Elamipretide may have therapeutic potential for children undergoing surgery with general anesthesia.

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May/June 2017 Newsletter

Look for us during 2017 at the following events:

·         Society for Pediatric Anesthesia 31st Annual Meeting, October 20th, 2017, Boston, MA

·         Society for Neuroscience in Anesthesiology and Critical Care, 45th Annual Meeting, October 19th – 20th, 2017, Boston, MA

·         American Society of Anesthesiologists, Anesthesiology 2017, October 21st – 25th, 2017, Boston, MA

Research News & Updates

Report from the 2nd International Conference on Pediatric Anaesthesia and Neurotoxicity – From GAS to Future Collaborative Trials, Genoa, Italy 13-14th of May 2017

Read more about the meeting outcomes

Editorial: Use of anesthetics in young children: Consensus Statement of ESA ESPA, EACTA, and EuroSTAR. Tom G. Hansen. Eur J Anesthesiol. 2017

Four European societies involved in pediatric anesthesiology say the evidence to support the FDA warning on use of anesthesia in children “is currently insufficient” and “not a warning they share.” Human studies do not support the cut off points of 3 hours and 3 years and there is no compelling evidence to change current practice. Counseling families on the risks of surgery and of avoiding or delaying necessary surgery remains important. Counseling families on anesthesia risks based on findings in animal studies–not confirmed in humans–may create undue anxiety and is ill advised.

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Editorial: Use of anesthetics in young children: Consensus Statement of ESA ESPA, EACTA, and EuroSTAR. Pediatric Anesthesia. 2017

This editorial in the Journal of Pediatric Anesthesia includes the identical consensus statement, described above, from four European societies involved in pediatric anesthesiology. They do not support the FDA’s recent warning about pediatric anesthesia and do not believe that clinicians should change current practice as a result. Instead, they emphasize the importance of family counseling on what is known about anesthesia risk based on human studies, and staying abreast of new developments in clinical research.

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Optimization of Pediatric PET/CT. Parisi MT, Bermo MS, Alessio AM, Sharp SE, Gelfand MJ, and Shulkin BL. May 2017

The authors provide a review of strategies for optimizing pediatric positron emission tomography, PET, and computed tomography, CT, radiation dose exposures while minimizing neurotoxic risk. The discussion emphasizes appropriate use of pediatric-specific CT imaging parameters and recommended radiotracer activities along with careful patient preparation and immobilization.

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Anesthetic Neurotoxicity in Congenital Hand Surgery: An Overview of the Evidence and Advice for Counseling Parents. Gart MS, Suresh S, and Adkinson JM. June 2017

The authors, plastic surgeons and anesthesiologists working in pediatric settings, discuss the importance of pre-operative family counseling on the risks of anesthesia. They examine reconstructive surgical timelines for common congenital hand problems in light of current scientific evidence in anesthetic neurotoxicity.

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Pediatric anesthesia and neurotoxicity: what the radiologist needs to know. Barton K, Nickerson JP, Higgins T, and Williams RK. May 2017

The use of MRIs in children is increasing along with a rise in the use of pediatric sedation. Is this causing an increase in long-term cognitive problems? The authors review related scientific findings with an emphasis on long-term developmental and cognitive outcomes while suggesting ways in which radiologists can use new technologies to reduce anesthesia risk.

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Neurodevelopmental outcomes of neonates undergoing surgery under general anesthesia for malrotation of intestines. Birajdar S, Rao S, and McMichael J. June 2017

Using a retrospective review, researchers study 33 neonates born at or above 32 weeks gestation who had early surgery to rotate their intestines under general anesthesia. Findings show that developmental outcomes from a single, short-term exposure to general anesthesia were similar to population norms, based on results of the Griffith Mental Development Scales at 1 year.

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Effect of Anesthesia on the Developing Brain: Infant and Fetus. Andropoulos DB. June 2017

The review summarizes rapid brain growth and development in the fetal/neonatal stages and presents relevant data on anesthetic neurotoxicity from animal models and recent clinical trials. The authors explore human trials with dexmedetomidine, a sedative, as a potential neuroprotectant.

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Anesthetic induced neurotoxicity in children. Bon-Nyeo Koo. June 2017

In his editorial, the author highlights 1) pre-clinical studies addressing the neuroprotective qualities of Apocynin; 2) neurotoxic effects of anesthesia on NMDA and GABA brain receptors; 3) mixed findings on anesthetic neurotoxicity from limited retrospective cohort studies using databases; and 4) prospective clinical research initiatives, including the GAS, PANDA, and MASK studies, using a comprehensive battery of neurocognitive tests.

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Safeguarding Infant Brains: A Multidisciplinary Challenge—Results of a Survey, Update on Current Scientific Evidence, and Recommendations on How to Deal with Possible Anesthetic Drug Neurotoxicity. Frank Weber, John Vlot, and Rene Wijnen. June 2017

How concerned are European pediatric surgeons about anesthesia-related neurotoxicity? Results of a survey, with 72 respondents found that 43% (31) have changed daily practice due to neurotoxicity concerns; 25% (18) are concerned; 40% (29) are neutral; and 11% (8) are not concerned. A majority call for more research, prioritizing prospective human studies above animal studies.

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Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon. Alam A, Suen KC, Hana Z, Sanders RD, Maze M, Ma D. March-April 2017

Dexmedetomidine (a sedative and pain medication) and xenon (a stable, inert gas) may be neuroprotective and less toxic as anesthetic agents to the developing brain, based on preclinical studies and early clinical observations. The authors review available research in an effort to provide new insight into the potential use of these agents with children in the pediatric surgical setting.

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General Anesthesia and Young Brain: What is New? Jevtovic-Todorovic V and Brambrick A. June 2017

The article provides a discussion of the latest developments in pre-clinical and clinical research relating to anesthesia-related pediatric neurotoxicity. The authors focus on outcome measures and exposure variables as useful tools in assessing cognitive and behavioral development.

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Visual recognition memory is impaired in rhesus monkeys repeatedly exposed to sevoflurane in infancy. Alvarado MC, Murphy KL, and Baxter MG. May 2017

Researchers administer three, 4-hour exposures of sevoflurane to monkeys on PN Days 7, 21, and 35. Results of visual paired comparison tasks show no memory impairment at 6-10 months, but there is significant memory impairment at 12-18 months and 24-30 months.

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Neuroprotection by plumbagin involves BDNF-TrkB-PI3K/Akt and ERK1/2/JNK pathways in isoflurane-induced neonatal rats. Yuan JH, Pan F, Chen J, Chen CE, Xie DP, Jiang XZ, Guo SJ, and Zhou J. July 2017

Can plumbagin, a plant-based substance with anti-inflammatory qualities, reduce isoflurane-induced neurotoxicity? Yes, according to this study in rats, given plumbagin orally between PN Days 2-6 and then exposed to 6 hours of isoflurane on PN Day 7. Plumbagin reduces isoflurane-induced brain cell death and helps maintain connections between neurons in the brain–in this case, in the BDNF-TrkB-PI3/Akt and ERK/JNK signaling pathways.

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Apocynin preserves glutamatergic neurons in the basolateral amygdala in mice with neonatal sevoflurane exposure. Sun Z, Satomoto M, Adachi YU, and Makita K. June 2017

A study in neonatal mice finds that Apocynin, a natural plant compound with anti-inflammatory qualities, administered on PN Day 6 and prior to sevoflurane, prevents sevoflurane-induced learning deficits and preserves neurons in the amygdala, a brain region, based on results of fear conditioning testing in the mice at maturity.

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Application of advanced preclinical models and methods in anesthetic neurotoxicity research. Wang C, Zhang X, and Liu F. May 2017

Can advanced pre-clinical research models and approaches, from the field of anesthesia-related toxicology, help to answer questions about the long-term effects of anesthesia on children? In their review, the authors explore the translational potential of unique pre-clinical models, including stem cell-derived cultures and organs-on-a-chip, which are in-vitro cells that mimic human organs.

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March/April 2017 Newsletter


Now available! The SmartTots Panel Livestream from the 2017 IARS Annual Meeting:

The Neuroscience of Brain Development: Opportunities and Alternative Perspectives for Pediatric Anesthesia Research.

Recording available at:

Look for us during 2017 at the following events:

  • ·         Society for Pediatric Anesthesia 31st Annual Meeting, October 20th, 2017, Boston, MA
  • ·         Society for Neuroscience in Anesthesiology and Critical Care, 45th Annual Meeting, October 19th – 20th, 2017, Boston, MA
  • ·         American Society of Anesthesiologists, Anesthesiology 2017, October 21st – 25th, 2017, Boston, MA

Research News & Updates

Can we reduce anesthesia exposure? Neonatal brain MRI: Swaddling vs. sedation, a national survey. Benjamin Heller, Francine Yudkowitz and Scott Lipson. May 2017

The authors describe results of a survey among 58 NICUs in the U.S. on the effectiveness of sedation agents for neonates having MRI brain scans.  Thirty-seven (37) NICUs use the feed and swaddle technique and most report a low level of imaging failure.  Nineteen (19) NICUs use sedation and two (2) use general anesthesia; they report no imaging failures.  In conclusion, feed and swaddle, the more popular technique should be the first-line method.  Sedation and general anesthesia should be used when feed and swaddle fails and in special circumstances.

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The Risk of Going Under: Research paints a complex picture of how surgery and anesthesia might harm the brain, particularly in the elderly. Andrea Anderson. March-April 2017

What about the risks for kids? The most robust clinical research shows no long-term cognitive consequences from general anesthesia. Clinical studies in children by Andrew Davidson in Melbourne and Lena Sun at Columbia are reassuring. They show no cognitive and behavioral deficits for anesthesia exposures of <1 hour and a median of 80 minutes, respectively. No blanket statement can be made about neural damage due to longer exposures for multiple and lengthy procedures.

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Why Some Pediatric Neurologists Are Concerned About a New FDA Warning About Anesthesia. Moran, Mark. March 2017

In response to criticism from the pediatric neurology community on the FDA’s recent Drug Safety Communication, Jeremy Kahn, FDA spokesman, responds: delaying some procedures is “clearly not an acceptable option…a single, short exposure to general anesthesia and sedation in infants or toddlers is unlikely to have negative effects on behavior or learning.” Dr. Santhanam Suresh, SmartTots Advisory Board, encourages physicians to use their best judgment, take care of the child, and do what is needed to make a diagnosis or treat an illness.

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Editorial: The new FDA drug safety communication on the use of general anesthetics in young children: what should we make of it? Andrew Davidson and Laszlo Vutskits. March 2017

These authors believe the FDA needed to issue a warning, but take issue with the alarming nature of its first sentence. They highlight the lack of evidence for a 3-year age limit, multiple v. single exposures, and confounding factors. Current evidence is not strong enough to support general guidelines on the effect of anesthesia on neurodevelopment. Colleagues are encouraged to focus on the evidence rather than the opening alarm.

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Anaesthetic considerations for surgery in newborns. CS Houck and AE Vinson. March 2017

In their review of animal and human studies, authors outline the effects of general anesthesia and anesthesia-related hemodynamic changes, relating to the flow of blood and oxygen on the developing brains of newborns. Current evidence in pre-clinical studies links all generally used anesthetics to neuronal cell death and signs of neurotoxicity, including the adverse effects of perioperative low blood pressure and hypocapnia, a lack of carbon dioxide in the blood.

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Sevoflurane decreases self-renewal capacity and causes c-Jun N-terminal kinase-mediated damage of rat fetal neural stem cells. Yang Z, Lv J, Li X, Meng Q, Yang Q, Ma W, Li Y, and Ke Z. April 2017

Investigators, exploring the effects of inhaled sevoflurane on FNSCs (fetal neural stem cells) and c-Jun N-terminal kinase, JNK (a protein that regulates cell growth, differentiation, survival, and death) find: 1.2% sevoflurane does not damage FNSCs; 2.4% decreases cell viability and increases cell death; 4.8% reduces cell proliferation, the proportion of undifferentiated cells, and damages FNSCs. JNK inhibition partially enhances cell viability and may be protective of FNSCs.

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Introduction to the special issue “Developmental neurotoxicity associated with pediatric general anesthesia: Preclinical findings.” Vesna Jevtovic-Todorovica, Philip J. Bushnell, and Merle G. Paule. February 2017

A special issue of the Journal of Neurotoxicology and Teratology, with 16 articles, provides guidance for future research on the mechanisms by which anesthesia acts in the developing brain and leads to long-term cognitive problems; provides new insight on the effects of general anesthesia on rapid synaptogenesis, receptor composition, and neurogenesis; and addresses therapeutic modalities. Seven articles are summarized in this issue of the SmartTots newsletter, the others have been addressed in previous issues. The editors anticipate that this Special Issue will support the development of research projects that will advance the field and improve best practices for the protection of our children’s health, a goal also shared by SmartTots.

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Anesthetic neurotoxicity: Apoptosis and autophagic cell death mediated by calcium dysregulation. Meirong Yang, MD, PhD and Huafeng Wei, MD, PhD. November 2016

In their review, the authors summarize current knowledge on two kinds of brain cell death: apoptosis, brain cell death due to injury, and autophagic cell death, a process of self-digestion by a cell’s own enzymes. Calcium dysregulation, a process associated with brain cell injury in anesthetic neurotoxicity, mediates both.

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Isoflurane exposure leads to apoptosis of neurons and oligodendrocytes in 20- and 40-day old rhesus macaques. Katie J. Schenning, Kevin K. Noguchi, Lauren Drew Martin, Francesca M. Manzella, Omar H. Cabrera, Gregory A Dissen, and Ansgar M. Brambrink. November 2016

Investigators compare brain cell death in 6-day-old v. 20 and 40-day-old monkeys exposed to 5 hours of isoflurane. Results from this study support the hypothesis that inhalational anesthetics, such as isoflurane, cause differential deleterious effects on the developing brain dependent on age and the stage of brain development. With the older monkeys, vulnerability diminishes for neurons and increases with oligodendrocytes.

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Neonatal inhibition of Na+-K+-2Cl−-cotransporter prevents ketamine induced spatial learning and memory impairments. Ryan A. Stevens, Brandon D. Butler, Saurabh S. Kokane, Andrew W. Womack, and Qing Lin. November 2016

Bumetanide (a diuretic used in treating fluid retention and swelling), when co-administered with ketamine, reduces ketamine-induced cognitive impairment in neonatal mice. Findings suggest bumetanide mitigates the neuro-excitotoxicity (which damages and kills nerve cells) associated with ketamine exposure.

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Neurogenesis and developmental anesthetic neurotoxicity. Eunchai Kang, Daniel A. Berg, Orion Furmanski, William M. Jackson, Yun Kyoung Ryu, Christy D. Gray, and C. David Mintz. October 2016

How does anesthesia interfere with the growth and development of neurons in the brain in the early postnatal period? Questions remain regarding the direct link between anesthesia exposure, brain changes, and long-term cognitive problems. In their review, the authors examine multiple anesthetics, and both in vivo and in vitro work, but say the causal link remains hard to find.

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The genetics of isoflurane-induced developmental neurotoxicity. Hyo-Seok Na, Nicole L Brockway, Katherine R Gentry, Elyce Opheim, Margaret M Sedensky and Philip G Morgan. October 2016

Using round worm larvae exposed to isoflurane, researchers find two critical pathways involved in anesthesia-induced neurotoxicity: DAF-2 dependent and endoplasmic reticulum (ER), where there are 44 mutations and drug-induced cell changes. The authors conclude that the neurotoxic effects of anesthesia in these pathways are completely preventable through manipulations at multiple points.

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Minimally invasive biomarkers of general anesthetic-induced developmental neurotoxicity. X. Zhang, F. Liu, W. Slikker Jr., C. Wang, and M.G. Paule. October 2016

Positron Emission Tomography, PET, is a non-invasive technology that can be used for measuring cellular processes associated with neurotoxicity, including cell proliferation, expression, death, and inflammation. Used widely with animals, PET is also in use with humans, and holds promise as a way to compare and translate findings from preclinical to clinical studies.

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A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies. Christine N. Zanghi and Vesna Jevtovic-Todorovic. December 2016

Using a holistic (whole-body) approach, this literature review examines mechanisms of anesthesia-induced neurotoxicity in early postnatal development of neuronal and non-neuronal cells. The authors, seeking ideas for future research, look at neural apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination, and the blood brain barrier.

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Funding Research to Ensure Pediatric Anesthesia Safety

January/February 2017 Newsletter

IARS SmartTots is conducting a search for a Program Officer

Look for us during 2017 at the following events:

·         SmartTots Panel at the IARS Annual Meeting, Sunday, May 7, 2017, 7:30 – 9:00 AM, EST

·         Society for Pediatric Anesthesia 31st Annual Meeting, October 20th, 2017, Boston, MA

·         Society for Neuroscience in Anesthesiology and Critical Care, 45th Annual Meeting, October 19th – 20th, 2017, Boston, MA

·         American Society of Anesthesiologists, Anesthesiology 2017, October 21st – 25th, 2017, Boston, MA

·         Second EuroSTAR – Pediatric Anesthesia and Neurotoxicity Scientific Conference, May 13 – 14, 2017, Genoa, Italy

Research News & Updates

Selective induction of IL-1β after a brief isoflurane anesthetic in children undergoing MRI examination. Whitaker EE, Christofi FL, Quinn KM, Wiemann BZ, Xia JC, Tobias JD, and Bissonnette B. January 2017

A study in 25 children, six months to 11 years, undergoing MRI scans, finds a 60-minute exposure to isoflurane increases interleukin-IL-1β, a marker for systemic inflammation associated with neurologic problems. There are no significant changes in tumor necrosis factor-α, interleukin-10, and vascular endothelial growth factors are undetectable.

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Letter to the Editor: Was isoflurane the only cause of IL-1β upregulation? Satoshi Ideno, Hiroyuki Seki, and Hiroshi Morisaki. February 2017

The authors question findings in the study by Whitaker et al. (above) citing lack of control for factors associated with an increase in serum interleukin-IL-1β/cytokine levels. These factors include intravenous catheter placement, laryngeal mask airway insertion, sterile needle insertion, and other minor stimuli known to influence stress response.

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Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon. Alam A, Suen KC, Hana Z, Sanders RD, Maze M, and Ma D. January 2017

This review of preclinical and clinical studies presents dexmedetomidine and xenon as effective anesthetics adjuvants, less toxic than most general anesthetics with neuroprotective qualities. While early human trials are promising, more clinical research is needed to corroborate and improve the effectiveness of these drugs in pediatric surgery.

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Anesthesia, Brain Changes, and Behavior: Insights from Neural Systems Biology. Colon E, Bittner EA, Kussman B, McCann ME, Soriano S, and Borsook D. February 2017

A critical review of pre-clinical and clinical data identifies subtle effects of early exposure to anesthesia on the developing brain in vulnerable populations. The authors summarize the underlying process in brain changes at the cellular and systemic level; they describe emerging neuroimaging techniques useful in evaluating and defining short and long-term changes in brain function.

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Pharmacological inhibition of PTEN attenuates cognitive deficits caused by neonatal repeated exposures to isoflurane via inhibition of NR2B-mediated tau phosphorylation in rats. Lei Tana, Xin Chen, Wei Wang, Jian Zhang, Shiyong Li, Yilin Zhao, Jintao Wang, and Ailin Luo. March 2017

A study using live, isolated brain cells from neonatal rats finds inhibition of the PTEN gene restores PSD-95 (a brain protein) involved in brain synthesis, reduces tau phosphorylation, and cognitive dysfunction associated with repeated exposure to isoflurane. Results suggest that PTEN is a promising target for therapeutic strategies aimed at reducing anesthesia-induced cognitive decline.

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Anesthetic-Related Neurotoxicity and Neuroimaging in Children: A Call for Conversation. Kara A. Bjur, MD; Eric T. Payne, MD, MPH; Michael E. Nemergut, MD, PhD; Danqing Hu, MD; and Randall P. Flick, MD, MPH. February 2017.

In response to the recent FDA Drug Safety Communication, a warning regarding repeated and prolonged exposure of children to general anesthesia, the authors summarize known risks of various anesthetic and sedation agents vis-a-vis pediatric neurotoxicity and neuroimaging.

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General anesthetics and cytotoxicity: possible implications for brain health. Armstrong R, Xu F, Arora A, Rasic N, and Syed N. April 2017

How does exposure to general anesthesia cause problems in thinking, learning, and memory in children and the elderly? What is the precise mechanism in the brain? Through a review, these investigators offer new insights, while emphasizing the urgent need for more research, especially highly controlled, prospective studies in humans.

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Scoping review: Awareness of neurotoxicity from anesthesia in children in otolaryngology literature. Earley MA, Pham LT, and April MM. February 2017

A search of otolaryngology databases from 2005 to 2015 yields scarce documentation on neurotoxicity as an outcome of inhalation and intravenous anesthesia in children. The authors offer no specific clinical recommendations, but call on Otolaryngologists to be aware of the concerns. They suggest further work toward better defining elective procedures, and to reassess the timing, frequency, and amount of anesthesia exposure for their pediatric patients.

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Neonatal anesthetic neurotoxicity: Insight into the molecular mechanisms of long-term neurocognitive deficits. Yu D, Li L, and Yuan W. March 2017

These scientists review the potential mechanisms for anesthesia-induced cognitive decline due to anesthesia exposure. There is a growing body of studies in animals linking early exposure to anesthesia with brain cell death in the immature brain, but a direct relationship with long-term cognitive decline remains controversial. Other factors, including impaired neurogenesis, abnormal synapse development, and alternations in brain pathways may be confounding factors in long-term neurocognitive dysfunction.

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Anesthesia and Developing Brains—Implications of the FDA Warning. Dean B. Andropoulos, MD, MHCM, and Michael F. Greene, MD. February 2017

This NEJM article is a response to the recent FDA Drug Safety Communication. The warning and timing takes clinicians and investigators by surprise. It raises concerns and questions among doctors, pregnant women, and parents that have no clear answers; provides no new alternatives to general anesthesia for vulnerable patients; puts children with life-threatening conditions at greater risk; and could cause delays for necessary surgical and diagnostic procedures resulting in adverse outcomes. The authors fully support the quest for high quality outcome studies on repeated and prolonged anesthesia exposure.

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Listen to an interview with Dr. Michael F. Greene regarding the recent FDA warning.

FDA warns of anesthesia risk in pregnant women, kids under 3. Robert Preidt. December 2016.

A CBS news article presents comments from Dr. Janet Woodcock, Director of the FDA Center for Drug Evaluation and Research, on the recent FDA Drug Safety Communication. While recognizing that anesthesia exposure may be medically necessary, the harms must weigh against the risk of not performing a procedure. She hopes the communication enables the most informed medical decisions possible on the use of anesthesia in young children and pregnant women.

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What parents should know about the use of general anesthesia in toddlers. Andriana Barton. March 2017

Responses from Health Canada, Canadian children’s hospitals and doctors to the FDA Drug Safety Communication. Canadian data from two large studies on the effects of anesthesia exposure in children under 2 years are reassuring. Parents are advised not to delay necessary surgery in light of the FDA warning, which they say is based on inconclusive data. Surgeries lasting more than 1 hour in young children are uncommon. The warning may cause undue alarm, leading to delays that result in adverse outcomes, particularly with life-threatening pediatric surgeries.

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Obstetricians balk at FDA warning on anesthesia in pregnant women. Ronnie Cohen. December 2016

A Reuter’s Health article describes objections from the American College of Obstetricians and Gynecologists, ACOG, to the recent FDA Drug Safety Communication on general anesthesia in pregnant women and children. “We were caught completely off guard…it’s unfortunate and inappropriate fear mongering…based solely on animal studies…with no data on pregnant women in human studies…may have a negative impact on women’s health.” ACOG has responded with a practice advisory.

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2016 Archive


IARS SmartTots is conducting a search for a Program Officer

Look for us during 2017 at the following events:

SPA-AAP Pediatric Anesthesiology 2017, March 3- 5, 2017, Austin, TX

IARS 2017 Annual Meeting and International Science Symposium, May 6-9, 2017, Washington, DC

Society for Pediatric Anesthesia 31st Annual Meeting, October 20th, 2017, Boston, MA

Society for Neuroscience in Anesthesiology and Critical Care, 45th Annual Meeting, October 19th – 20th, 2017, Boston, MA

American Society of Anesthesiologists, Anesthesiology 2017! October 21st – 25th, 2017, Boston, MA

Join us for the Second EuroSTAR – Pediatric Anesthesia and Neurotoxicity Scientific Conference:

May 13 – 14, 2017, Genoa, Italy

Research News & Updates

FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women

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In a joint statement, the IARS/SPA/ASA/AAP/SOAP/CCAS/PALC/SPPM/ASPA/SMFM respond to the FDA announcement

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Current thinking regarding potential neurotoxicity of general anesthesia in infants. McCann, Mary Ellen; de Graaff, Jurgen, January 2017

The GAS and PANDA studies offer promising results for short-duration use of general anesthesia in human children. The 5-year outcomes due in 2018 are critical. Aside from this evidence, there are limited retrospective cohort studies and they have conflicting results. Studies in animals show that general anesthesia damages the developing brain. Cell research in animals associates early exposure to virtually all general anesthetics with brain cell death and neuron damage. While awaiting greater clarity in clinical evidence, anesthesiologists are encouraged to talk over pediatric anesthesia use with families, helping them to weigh the risks and benefits of various procedures.

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The Neurotoxicity of General Anesthetic Drugs: Emphasis on the Extremes of Age. Biddle C; Ford V., January 2017

The chapter reviews scientific literature on acute and long-term effects of general anesthesia on the central nervous system of children. The extrapolation of animal research to humans is “complicated and tenuous at best.” Human, retrospective, observational, case-controlled, and cohort-matched studies do not permit cause and effect interpretations. Today’s science needs controlled studies; there are currently too many uncontrolled variables. The authors highlight SmartTots, the GAS and PANDA trials, the Mayo Anesthesia Safety in Kids Study, and list five obstacles to achieving valid research conclusions.

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Association of Anesthesia and Surgery During Childhood With Long-term Academic Performance. Glatz P, Sandin RH; Pedersen NL; Bonamy A; Eriksson LI; Granath F., January 2017

A Swedish cohort study of 33,514 children with one anesthesia exposure for surgery before age 4 finds a mean difference of .41% for lower grades at age 16 and 97% for IQ scores at age 18. This overall difference is less than the differences associated with sex and maternal education level. The authors say that low overall differences in academic performance after childhood exposure are “reassuring.”

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Anesthesia Kills Brain Cells, but What Does It Mean? Sall, Jeffrey, December 2016

The editorial compliments Jiang et al. for their ongoing work in pediatric anesthesia neurotoxicity research, highlighting the team’s in-depth study* on brain cell death after early exposure to anesthesia.  Using a genetic fate mapping approach with neonatal mice, Jiang finds the dentate gyrus, small cells involved in early development of the hippocampus, can recapture normal neuron numbers after a single exposure to isoflurane; they are more resilient than other areas of the brain which show permanent neuron loss. While sparking new questions, these findings advance knowledge on the association of anesthesia-induced brain cell death to active stages of neurogenesis, lost connections in brain pathways, and cognitive deficits.

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* Original article published in the September/October SmartTots Newsletter: Read More

Lasting impact of general anesthesia on the brain: mechanism and relevance. Vutskits, Laszlo; Xie, Zhongcong, November 2016

How are the mechanisms of general anesthesia induction and reversal linked to the mechanisms of long-term cognitive dysfunction? In their data review, the authors address this question in general and pose additional questions for future research: where do molecular, cellular, and systemic changes overlap? How is general anesthesia induction and reversal involved in altering synaptic connectivity? Why are neuronal structures more vulnerable at certain stages of development? What mechanisms link the physiological effects of general anesthesia to morphological and functional changes in the brain? Are there therapeutic or protective aspects to general anesthesia as some studies indicate?

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The Relevance of Anesthetic Drug-Induced Neurotoxicity. Hansen TG; Engelhardt T, Weiss M., November 2016

Proving the association of early anesthesia exposure in children with long-term neurocognitive deficits has many challenges: in translating findings from animals to humans; in defining appropriate neurocognitive outcome measures, and in conducting sufficiently robust cohort studies. Taking exception, the author praises the Swedish cohort study from Glatz et al.* for findings that are in line with those of the GAS and PANDA studies. This author concludes that it is unlikely that early anesthesia exposure in children will correlate with long-term neurocognitive outcomes.

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*The Glatz study is available here: Association of Anesthesia and Surgery During Childhood With Long-term Academic Performance

Anesthetic Neurotoxicity: New Findings and Future Directions. Montana, Michael C.; Evers, Alex S., November 2016

In their update, the authors identify challenges in translating findings from anesthesia neurotoxicity research in animals to human children. Early results from GAS and PANDA trials are “reassuring” for short duration exposure. Clinical research needs to answer relevant questions about longer duration or repetitive anesthetic exposure and use of anesthesia in healthy children who do not require multiple anesthetics. Does the anesthetic regimen or the pathophysiologic background of patients cause neurocognitive deficits? The article poses this and eight additional research questions.

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Is a short anesthetic exposure in children safe? Time will tell: a focused commentary of the GAS and PANDA trials. Chinn, Gregory A.; Sasaki Russell, Jennifer M.; Sall, Jeffrey W., October 2016

Scientists are cautiously optimistic about early results from the GAS and PANDA trials, but say there are many unanswered questions: With GAS, what will IQ tests show when subjects are 5 years old? With PANDA, was the sample a true reflection of the population or skewed to a higher socio-economic level? Will cognitive problems appear later in life?

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Do anesthetics harm the developing human brain? An integrative analysis of animal and human studies. Lin, Erica P.; Lee, Jeong-Rim; Lee, Christopher S.; Deng, Meng; Loepke, Andreas W., October 2016

At what age is the developing brain most vulnerable to the effects of anesthesia? Beyond a certain age, are children’s brains safe from long-term damage from anesthesia? Is there a specific duration of anesthesia exposure with no damaging effects to the brain? The authors find no clear answers to these questions after integrating preclinical data on brain structure and function with results from neurocognitive human studies. They urge expanded efforts to find safer anesthetic techniques and mitigating strategies that lessen long-term brain damage.

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Role of mitochondrial complex I and protective effect of CoQ10 supplementation in propofol induced cytotoxicity. Bergamini, C.; Moruzzi, N.; Volta, F. et al, August 2016

Mitochondria is an energy powerhouse in cells of the body and brain. In this study, researchers aim to find the main mitochondrial respiratory chain target of propofol toxicity. Results show the target is Complex I, the first enzyme in the mitochondrial chain, on the Q module, where propofol impairs oxygen use. CoQ10, an antioxidant that supports cell life, appears to mitigate the toxic effects of propofol by preserving cell energy; it has therapeutic potential for reducing propofol-induced neurotoxicity.

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Maternal anesthesia and fetal neurodevelopment. Palanisamy, A, April 2012

Obstetric anesthesiologists discuss challenges in defining the effects of maternal anesthesia on the human fetus in each trimester of pregnancy. They highlight the second trimester, a period of rapid brain cell growth as more vulnerable than previously thought. The science shows no one anesthetic agent to be better for a pregnant woman in terms of fetal effects. Propofol holds promise. Randomized controlled clinical trials present ethical dilemmas. The authors encourage retrospective analysis of existing data for long-term effects on children exposed to anesthesia in utero for non-obstetric surgery and fetal interventions; and for children exposed to GABAergic drugs and nitrous oxide for maternal sedation during pregnancy, labor, and delivery.

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Editor’s note: this study was completed in 2012, but we are publishing it now due to the FDA’s recent safety communication about general anesthetics and sedation drugs during pregnancy.

Caffeine combined with sedative/anesthetic drugs triggers widespread neuroapoptosis in a mouse model of prematurity. Cabrera, Omar Hoseá; O’Connor, Shawn David; Swiney, Brant Stephen, et al, December 2016

When co-administered with midazolam, ketamine, or fentanyl, does caffeine increase neurotoxicity and brain cell death? Yes, according to this study in postnatal mice. Scientists find activated caspase 3 levels and a higher number of AC3 positive cells in five areas of the brain, including the neocortex, hippocampus, caudate, thalamus, and colliculi. Caffeine appears to have a “supra-additive effect.”

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Exposure to sevoflurane anesthesia during development does not impair aspects of attention during adulthood in rats. Murphy, Kathy L; McGaughy, Jill; Croxson, Paula L; Baxter, Mark G, December 2016

Do single or repeated exposures to general anesthesia cause long-term attention deficits? In this study, neonatal rats receive 2.5% sevoflurane for two hours at PN Day 7 or PN Days 7, 10 and 13, followed by sustained attention and attention-shifting tasks in adolescence. Findings show no anesthesia-induced impairments in attention processing.

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Review of preclinical studies on pediatric general anesthesia-induced developmental neurotoxicity. Walters, Jennifer L.; Paule, Merle G., November 2016

A review of 211 preclinical studies examines the effects of general anesthesia on neurobehavioral development. The authors index the effects of anesthetic agents on neurotoxicity and functional outcome and review protective compounds. The extent to which the damaging effects of general anesthesia on animal brains generalize to humans is unclear. Future studies should describe precise circumstances under which general anesthetics impair the developing brain; develop effective prevention and treatment strategies; and determine the extent to which neurotoxic effects and preventive strategies generalize to clinical settings.

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Neonatal Repeated Exposure to Isoflurane not Sevoflurane in Mice Reversibly Impaired Spatial Cognition at Juvenile-Age. Liu, J.; Zhao, Y.; Yang, J. et al, November 2016

A study in postnatal rats compares the effects of sevoflurane vs. isoflurane on long-term neurotoxicity. Using Morris Water Maze, Western Blot, and Nissl and TUNEL staining, scientists find spatial cognitive impairment and greater neurodegeneration with isoflurane. There are, however, differing degrees of brain cell death and damage to hippocampal neurons with both anesthetics after repeated inhalations.

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Special Newsletter Edition: 2016 PANDA Symposium

Special Newsletter Edition: 2016 PANDA Symposium pandastudylogo

The 5th Annual PANDA Symposium was held at the Morgan Stanley Children’s Hospital of New York on April 16-17, 2016. All of the articles in this Special Edition of the SmartTots Newsletter are summaries of the content presented at the PANDA Symposium and were published in a supplement of the Journal of Neurosurgical Anesthesiology. The PANDA Symposium is hosted by the PANDA Study investigator team. It is a key forum for investigators and other professionals, gathering a diverse group of people with a shared concern about the neurotoxicity of anesthetics to the developing brain as demonstrated in animal studies and the possibility that anesthetics may be neurotoxic to the developing brain in humans. Attendees included clinicians, preclinical and clinical researchers and representatives from the Food and Drug Administration and the National Institutes of Health.

Introduction to the Proceedings of the Fifth PANDA Symposium on “Anesthesia and Neurodevelopment in Children. October 2016

The two-day PANDA Symposium on April 16 and 17, 2016 at Morgan Stanley Children’s Hospital in New York, funded in part by SmartTots, captured the state of current knowledge and future priorities for pre-clinical and clinical research on pediatric anesthetic neurotoxicity, as reflected in these proceedings. They include 12 peer-reviewed articles, four on original research, and 7 reports reflecting presentations at the Symposium. This short introduction provides an overview of the symposium program.

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Report on the Fifth PANDA Symposium on “Anesthesia and Neurodevelopment in Children.” October 2016

A summary of PANDA Symposium proceedings: the PANDA study and future directions; update on pre-clinical and clinical studies; research on drug safety and anesthetic neurotoxicity; what’s next in anesthetic neurotoxicity research; lessons learned: studying the vulnerable brain and engaging the stakeholders panel discussions.

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Summary of the Update Session on Clinical Neurotoxicity Studies. October 2016

An update on five ongoing clinical studies: General Anesthesia Compared to Spinal Anesthesia (GAS Study); Toxicity of Remifentanil and Dexmedetomidine (T-Rex Trial); Mayo Anesthesia Safety in Kids (MASK Study); the University of California San Francisco Human Cohort Study; and the Columbia University Medical Center Neonatal Magnetic Resonance Imaging Study. The authors discuss the contributions and limitations of these studies, how they fit into the published literature, and the questions that remain. The author acknowledges that even upon completion of these studies there will remain significant gaps in knowledge that will require further study.

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Molecular Mechanisms of Anesthetic Neurotoxicity: A Review of the Current Literature. October 2016

In their literature review, the authors examine current thinking on molecular mechanisms of anesthetic toxicity in the developing brain, including effects on cell death pathways, growth factor signaling systems, NMDA and GABA receptors, mitochondria, and epigenetic factors. The authors evaluate the evidence for each of these mechanisms and attempt to draw connections between them. Findings show promising avenues of research, but no consensus on a definitive mechanism of injury. The authors emphasize the need for a definitive phenotype of injury.

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What Next After GAS and PANDA? August 2016

Experts in anesthesiology, neuropsychology, and epidemiology, convening in a small group session, do not agree that the current body of pediatric anesthesia neurotoxicity literature establishes a direct relationship between anesthesia exposure and long-term neurodevelopmental problems in children. The scientific community needs more clinical research and observational studies to guide research questions, particularly on length of exposure, dosing, and the effect of comorbidities.

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Biomarkers, Genetics, and Epigenetic Studies to Explore the Neurocognitive Effects of Anesthesia in Children. August 2016

A focus group agrees that translational research in pediatric anesthetic neurotoxicity needs new biomarkers (measurable indictors). Participants call for the creation of well-defined intermediate phenotypes (observable traits) and support advanced neuroimaging as a feasible and reasonable modality, and biomarker. This effort promises to advance research, improve anesthesia safety and effectiveness, and clarify the effect of anesthesia neurotoxicity on neurodevelopment.

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Mechanisms for Research Support. October 2016

A session entitled “The Way Forward” presents three talks: 1) the mission of ACTTION, a public-private partnership with the FDA, supporting research on pain and analgesics; 2) NIH funding for future studies in neurocognitive development after exposure to anesthetics; and 3) how the PANDA group might better craft public messages on the effects of analgesics on neurocognitive development. A need for the research community to come together was identified, with efforts focused on a common goal and the proper expenditure of precious resources.

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Lessons Learned: Studying the Vulnerable Brain. October 2016

Four notable neuroscientists address current concepts and research in neurodevelopment, highlighting periods of particular susceptibility and ways in which neural connectivity and systemic functioning is affected. Their presentations include an overview of normal and abnormal neural physiology with identification of vulnerable neurodevelopmental processes; research investigating the brain connectome (map of brain connections) in congenital cardiac patients; and identification of potential modifying factors, like physical activity, which may reduce injury.

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Optimal Timing of Surgical Procedures in Pediatric Patients. October 2016

In this symposium on pediatric anesthetic neurotoxicity, The American Academy of Pediatrics Surgical Advisory Panel addresses optimal surgical timing as well as a “critical window” for surgery on a specialty-specific basis. An ad hoc panel of pediatric surgical experts representing general surgery, urology, neurosurgery, and ophthalmology discusses the benefits of early intervention v. potential anesthetic risk along with parental concerns, and the need for continued interdisciplinary collaboration.

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Use of Anesthesia for Imaging Studies and Interventional Procedures in Children. August 2016

A panel of specialists from nonsurgical pediatric disciplines (anesthesiology, radiology, neurology, gastroenterology, oncology, cardiology, critical care) reviews the use of anesthesia in their practices. They address parental concerns over possible neurodevelopmental effects of early childhood anesthetic exposure and the effect of these concerns on discussions with families regarding risks and benefits of imaging studies/ interventional procedures involving sedation or anesthesia. The session emphasized the need for guidelines to reduce inappropriate or unnecessary imaging unlikely to aid diagnosis or guide treatment.

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Sevoflurane Impairs Growth Cone Motility in Dissociated Murine Neurons. October 2016

Using cultures from embryonic mouse brains, researchers explore the effects of sevoflurane on the neuronal growth cone (tip) at the ends of axons and dendrites, responsible for the growth that supports connections between neurons. Study results show sevoflurane interferes with the growth cone’s ability to move spontaneously and actively, an important process in the formation of brain circuits. This interference may occur through an action on p75NTR, a nerve receptor.

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Analysis of MRI Utilization in Pediatric Patients. August 2016

Using the New York State Inpatient Database and State Ambulatory Surgery and Services Database on MRI performed in children under the age of 18 years from 2005 to 2011, the authors analyze MRI utilization in a pediatric population and associated use of anesthesia for ambulatory MRI. Findings show a significant association between MRI and anesthesia use, especially in younger children. This calls for more discussions with both clinicians and families on the risks and benefits of anesthesia for the child having an MRI.

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IARS thanks the FDA for its renewed support of the

SmartTots Public-Private Partnership!

Look for us during 2017 at the following events:

SPA-AAP Pediatric Anesthesiology 2017, March 3- 5, 2017, Austin, TX

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity, May 13 – 14, 2017, Genoa, Italy


Research News & Updates

Neurodevelopmental Assessment in Kindergarten in Children Exposed to General Anesthesia before the Age of 4 Years. October 2016.

In a retrospective cohort study, scientists give the Early Developmental Instrument (EDI) to 4,470 kindergarteners with early exposure to a single or multiple doses of general anesthesia. For children receiving a single or multiple exposures at birth to age two, findings show no neurodevelopmental deficits. Among children exposed between ages two and four, deficits appear with a single exposure, but not with multiple exposures, surprisingly.

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The effect of anaesthesia on the infant brain. September 2016

The author describes problems in translating findings on anesthesia exposure in animal studies to human children, despite reassuring results in the PANDA and GAS studies.  He voices concerns about recommendations that are unspecific, difficult, and not based on sufficient evidence, such as avoiding unnecessary anesthesia in children and procedures before a certain safe age.  A single procedure lasting less than one hour should not be delayed.  The delay of a longer procedure should be balanced with the risk due delay.  The anesthesiologist seeing a greater risk should not alter technique in such a way as to replace the theoretical risk of neurotoxicity with a greater risk of cardiovascular or respiratory problems, particularly in neonates and infants.

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Intelligence quotient scores at the age of 6 years in children anaesthetised before the age of 5 years. September 2016

This analysis examines the association of independent variables, including anesthesia before age five, with non-verbal cognition in a sample of 3,441 six-year-olds. Findings show a lower mean IQ score for children born before 32 weeks gestation; with low maternal IQ and education; with maternal smoking during pregnancy; and for all children exposed to anesthesia before age 5. The authors note that only 415 children, 12% of the sample, had anesthesia exposure and data are missing for this group. The anesthesia includes propofol, sevoflurane, isoflurane, fentanyl, sufentanil or alfentanil.

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Naringenin pre-treatment inhibits neuroapoptosis and ameliorates cognitive impairment in rats exposed to isoflurane anesthesia by regulating the PI3/Akt/PTEN signalling pathway and suppressing NF-κB-mediated inflammation. October 2016

Does naringenin, a flavonoid in fruits with antioxidant and anti-inflammatory qualities, help reduce isoflurane-induced brain cell death and cognitive impairment? Yes, according to this study in neonatal rats. Using TUNEL assay and blot analysis, the authors also find naringenin improves learning capacity and memory retention, and modulates signaling pathways in the brain.

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Dexmedetomidine pretreatment attenuates propofol‑induced neurotoxicity in neuronal cultures from the rat hippocampus. October 2016

This in vitro animal study in brain cells of baby rats shows that pretreatment with dexmedetomidine (DEX) counters propofol-induced brain cell death, increases the viability of young hippocampal neurons, and increases the expression level of p-CREB, BCL-2, and BDNF, proteins in the brain associated with cell growth and death. Using cell counting kits and flow analysis, the authors conclude that DEX has a direct neuroprotective effect.

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The Fas Ligand/Fas Death Receptor Pathways Contribute to Propofol-Induced Apoptosis and Neuroinflammation in the Brain of Neonatal Rats. October 2016

An experimental study in baby rats looks at the effect of propofol at PN Day 7 on the expression of the Fas receptor and Fas Ligand, both potential players in a cell-death pathway in the brain. Results show greater, abnormal expression of the Fas receptor, Fas Ligand, and caspase-8 proteins in the thalamus than the cortex with abnormal expression in the Bcl-2 gene and caspase-9 protein in the cortex. There is upregulation (hypersensitivity) associated with inflammation of caspase-1 and IL 1β cytokine transcription, along with activation of the microglia’s immune cells. At PN Days 35 and 60, the rats display significantly higher motor activity in field tests.

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Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity. September 2016

Researchers use genetic-fate-mapping with mice to explore the effect of 1.5% isoflurane for six hours on the brain’s granule cells (baby neurons) treated with green fluorescent protein (GFP), which lights up and shows cell activity. Isoflurane exposure increases cell death in some of the GFP-treated cells right after exposure. By Day 60, however, the granule cells in both the control and treated mice appear equal in number. This suggests a restorative function for the dentate gyrus, the brain structure that houses the granule cells.

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Early-life single-episode sevoflurane exposure impairs social behavior and cognition later in life. September 2016

Using Active Place Avoidance (APA) and Novel Object Recognition (NOR) tests, scientists assess the effect of a single, two-hour dose of sevoflurane on 7-day-old mice—results show deficits in learning and memory.  At one to five months, the mice receive neuro-psychiatric-like/behavioral tests—results show deficits in pushing, crawling, responding to new objects, and sniffing time.  Overall findings suggest a single dose of sevoflurane impairs cognition and social interactions later in life.

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Carbon monoxide and anesthesia-induced neurotoxicity. September 2016

This extensive literature review, with 106 references, addresses the effect of low-dose exposure to carbon monoxide (CO), a gas, commonly used in infants and children having general endotracheal anesthesia. The authors discuss CO’s biological activity in and effect on the brain; the neurotoxicity of other anesthetic agents, including sevoflurane; and CO’s role in reducing anesthesia-induced neurotoxicity.

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Astragaloside IV protects new born rats from anesthesia-induced apoptosis in the developing brain. September 2016

Astragaloside IV is a molecule from an herb used in Chinese medicine with healing and anti-aging properties, including in vitro cell growth in animal models. In this study, scientists pretreat newborn rats with astragaloside IV (AS IV) or an oral solvent for three days prior to sevoflurane exposure. Results are favorable for AS IV, which significantly inhibits anesthesia-induced cell death and reduces oxidative stress and inflammation in the brain’s hippocampus.

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Isoflurane provides neuroprotection in neonatal hypoxic ischemic brain injury by suppressing apoptosis. September 2016

Using an in vitro slice of animal brain, scientists simulate brain hypoxia (lack of oxygen) and then administer isoflurane to explore its neuroprotective effect. The authors find isoflurane preserves cell population; reduces brain cell death and the potential for hypoxic injury; controls the release of damaging amino acid neurotransmitters; and stops the swelling of neurons in the brain’s hippocampus.

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Long-lasting behavioral effects in neonatal mice with multiple exposures to ketamine-xylazine anesthesia. September 2016

A study in baby mice examines the effect of single v. multiple doses of ketamine-xylazine, a combination anesthetic, at PN Days 7, 9, and 11. Behavioral tests at one month associate multiple doses with deficits in object recognition, sociability, social novelty preference, fear response, and enzyme function for synaptic connections and later learning. The single dose is associated with deficits in fear response only.

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Altered hippocampal microRNA expression profiles in neonatal rats caused by sevoflurane anesthesia: MicroRNA profiling and bioinformatics target analysis. September 2016

MicroRNAs (miRNAs) are small molecules in human and animal genes involved in cell growth, mobility, and death. To clarify the role of miRNA expression in sevoflurane neurotoxicity, the authors conduct a bioinformatics analysis using brain samples from neonatal mice 24 hours after sevoflurane exposure. Analysis of 85 targets in nine deregulated miRNAs associates aberrant miRNA expression with synaptic dysfunction, hippocampal neurogenesis, and behavioral defects.

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Volatile Anesthetics Transiently Disrupt Neuronal Development in Neonatal Rats. August 2016

Do isoflurane, sevoflurane, and desflurane disrupt brain development and lead to long-term neurobehavioral defects? To answer, the authors give Bromodeoxyuridine (BrdU), a synthetic substance that helps mark and show changes in cells, to baby rats on PN Day 1, followed by a two-hour exposure to one of the three anesthetics on PN Day 2. Results of assays and microscopy on PN Day 7 and 14, and behavioral tests at 6 weeks and 6 months, show that isoflurane and desflurane cause interim disruption in hippocampal neuronal development, which later resolves, with no significant long-term effects on learning and memory. Sevoflurane has no effect.

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Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats. August 2016

Findings show that 40 mg ketamine administered to baby rats at PN Day 7, in four injections, within one-hour intervals, interferes with hippocampal neurogenesis (the growth of neurons in the brain) and leads to long-term problems in neurocognition. More specifically, ketamine inhibits the growth of neural stem cells, decreases astrocytic differentiation (healthy development of cells that protect the brain’s neurons), and leads to long-term deficits in the brain’s spatial reference memory.

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Look for us in 2016 at the following events:

  • Society for Pediatric Anesthesia, 30th Annual Meeting, October 21st, 2016, Chicago, IL
  • Society for Neuroscience in Anesthesiology and Critical Care, 44th Annual Meeting, October 20th – 21st, 2016, Chicago, IL
  • American Society of Anesthesiologists, Anesthesiology 2016! October 22nd – 26th, 2016, Chicago, IL

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity, June 8 – 10, 2017, Genoa, Italy


Research News & Updates

Anesthetic Neurotoxicity Meets Big Data: Reasons to be Cheerful? August 2016

This editorial praises the O’Leary study (JAnes/Aug 2016) as a large well-designed population-based outcome study with hopeful findings regarding the neurotoxic effects of short-duration exposure to anesthesia in young children. The authors comment on strengths and weaknesses of experimental animal studies and randomized clinical trials, and the need to adjust for co-morbidities and factors unrelated to anesthesia exposure.

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A Population-based Study Evaluating the Association between Surgery in Early Life and Child Development at Primary School Entry. August 2016

The authors look for developmental vulnerability reflecting scores in the bottom 10th percentile on developmental tests among 28,366 primary school children with early exposure to anesthesia. 25.6% of these children fall into the vulnerable range in comparison to their unexposed cohort. Exposure at age two or later has a small risk of lower developmental scores; exposure before age two does not.

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Preparing Your Child for Surgery: Questions to Ask the Physician Anesthesiologist. July 2016

The American Society of Anesthesiologists reassures parents that anesthesia in children is generally safe with very low risk. The organization encourages good communication between physicians and parents and offers seven questions every parent should ask their child’s anesthesia provider before any procedure.

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Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane‑induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways. August 2016

A study in neonatal rats finds the bioactive compound caffeic acid phenethyl ester, CAPE, reduces brain cell death caused by sevoflurane. For rats receiving both CAPE and sevoflurane, CAPE is protective by helping to modulate and regulate neurotoxic activity in brain enzymes, proteins, and pathways.

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Baicalin Attenuates Ketamine-Induced Neurotoxicity in the Developing Rats: Involvement of PI3K/Akt and CREB/BDNF/Bcl-2 Pathways. August 2016

Scientists conclude that baicalin, a flavonoid (plant pigment) and therapeutic agent, administered prior to ketamine in baby rats helps prevent sevoflurane-induced cell degeneration and death in the cortex and hippocampus by controlling aberrant changes in critical brain proteins and pathways.

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Dexmedetomidine-Induced Neuroapoptosis Is Dependent on Its Cumulative Dose. August 2016

A study using in vivo neuronal cells from baby rats associates cumulative doses of Dexmedetomidine (Dex) with increasing cell death; finds the higher doses negatively affect prosurvival kinases. Authors conclude that Dex promises neuroprotection at lower doses and is less toxic than ketamine alone or in combination with Dex.

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Recent Insights into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies. August 2016

The authors draw conclusions about and describe protective strategies against the developmental neurotoxicity of propofol in children through this extensive literature review of studies in animals, animal cell cultures, and human stem cell neuronal cultures. Discussion highlights mechanisms of propofol, relationship to neuronal survival, dendrite disruption, calcium overload, inflammation, mitochondrial fission, and more.

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From Drug-Induced Developmental Neuroapoptosis to Pediatric Anesthetic Neurotoxicity-Where Are We Now? August 2016

Scientists review influential research to date, mostly in animals, and limited clinical studies on drug-induced brain cell death in the fetal and neonatal periods.  They highlight findings in animals that implicate GABA agonists and NMDA antagonists, commonly used in pediatric anesthesia, for increased levels of neuronal cell death; report on psychoactive drugs for altering neurodevelopment and synaptic plasticity; and emphasize the need for more preclinical and clinical research, including long-term outcome studies in humans.

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Pediatric anesthesia and neurotoxicity: can findings be translated from animals to humans? July 2016

The authors acknowledge that most current knowledge regarding the neurotoxic effects of anesthesia on the brain comes from animal studies; findings are difficult to extrapolate to human children. Nonetheless, animal studies should continue, given what they teach us about anesthesia and how it works in the brain. However, the authors urge that future studies follow the ARRIVE guidelines to improve quality and standardization. Human studies, equally important, should continue alongside animal research, helping to prove that what is true in animals is true for children–or not.

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Reactive Oxygen Species-mediated Loss of Phenotype of Parvalbumin Interneurons Contributes to Long-term Cognitive Impairments after Repeated Neonatal Ketamine Exposures. July 2016

Scientists give learning and memory tests to adolescent male rats administered Apo, an oxidase inhibitor, along with ketamine in their early postnatal days. Findings show Apo reduces brain abnormalities and cognitive impairments associated with ketamine-induced neurotoxicity and oxidative stress.

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Heightened stress response and cognitive impairment after repeated neonatal sevoflurane exposures might be linked to excessive GABAAR-mediated depolarization. July 2016

Prior to administering sevoflurane, researchers give baby rats bumetanide, a diuretic, and find that it inhibits the increase in the brain hormone corticosterone, helps to control stress response, and reduces learning and memory impairments associated sevoflurane administration.

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Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/Akt/Gsk-3β signaling disruption, and juvenile cognitive deficits in neonatal rats. July 2016

In this study, seven-day-old rats are pretreated with Dexmedetomidine (Dex) prior to repeated injections of propofol. Dex reduces propofol-induced changes in the brain’s hippocampus and deficits in spatial learning and memory.

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Anesthetic Sevoflurane Causes Rho-Dependent Filopodial Shortening in Mouse Neurons. July 2016

Researchers explore the effect of sevoflurane and drebrin antibodies on brain synapses, particularly hippocampal neurons in fetal mice. Rho kinase inhibitor reverses sevoflurane-induced shortening of the neuron’s filopodia and dentritic spines by fetal day 7. Shortening of cluster-type filopodia persists by fetal day 9, due to drebrin immunoreactivity. Findings highlight the role of RhoA/Rho kinase signaling and drebrin impairment in synapse formation.

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Subclinical concentrations of sevoflurane reduce oxidative stress but do not prevent hippocampal apoptosis. July 2016

Does sevoflurane in low doses of 0.3, 1.3, or 2.3% at postnatal day 7 have a neuroprotective effect on the brains of baby mice? Researchers measure stress markers in plasma and the hippocampus; look for brain cell death; and examine long-term behavioral effects at postnatal day 28. Findings show that early exposure to low doses of sevoflurane can reduce oxidative stress, but does not prevent brain cell death nor affect long-term memory.

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Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment. May 2016

Using zebrafish embryos, scientists confirm the ability of ALCAR, a substance produced naturally in the body and often used as a dietary supplement, to reverse the neuro and developmental toxicity of ketamine and ketamine plus verapamil. Findings show that ALCAR is blocked downstream by oligomycin A, an inhibitor of ATP synthase.

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Look for us in 2016 at the following events:

Society for Pediatric Anesthesia 30th Annual Meeting, October 21st, 2016, Chicago, IL

Society for Neuroscience in Anesthesiology and Critical Care, 44th Annual Meeting, October 20th – 21st, 2016, Chicago, IL

American Society of Anesthesiologists, Anesthesiology 2016! October 22nd – 26th, 2016, Chicago, IL

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity, June 8 – 10, 2017, Genoa, Italy


Research News & Updates

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. June 2016

A cohort study of 105 pairs of siblings–one exposed to anesthesia in infancy for hernia surgery and one not–reveals no significant differences in IQ scores and other neurocognitive tests/behavioral assessments at the mean age of 10.6 years.

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SmartTots responds to the release of the PANDA Study results. June 2016

SmartTots praises the promising results from the recently released PANDA study, which finds no significant cognitive differences between healthy children, exposed to a single short-duration dose of general anesthesia before age three, and their unexposed siblings at ages eight to 15. Siblings were assessed for memory, learning, attention, language, and behavior. SmartTots partially funded the study, published in the June 7, 2016 issue of JAMA.

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Is anesthesia bad for children’s brains? June 2016

A prominent anesthesiologist responds to parents’ concerns, underscoring many questions that remain about the potentially damaging effects of anesthesia on the brains of infants and children who must undergo surgery. He highlights the flaws in current research, much of which is retrospective in nature; the promise of two, large prospective studies in human children; and encourages readers to follow the progress of SmartTots.

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Post-anesthesia AMPA receptor potentiation prevents anesthesia-induced learning and synaptic deficits. June 2016

Scientists working with baby rats exposed to general anesthesia find the drug CX546, an AMPAkine, known to stimulate brain receptors, counters the neurodegenerative effects of general anesthesia by helping to protect the brain’s dendritic spine plasticity.

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A pilot study of dexmedetomidine sedation and caudal anesthesia for inguinal hernia repair in infants. June 2016

These researchers found that dexmedetomidine (dex) sedation with caudal anesthesia is a feasible alternative to general endotracheal anesthesia for uncomplicated inguinal hernia surgery in neonates. Their chart review of 50 neonates given two mcg of dex for ten minutes followed by 1 mcg over the next ten minutes yields an 86% success rate; 14% of neonates needed additional sevoflurane or nitrous oxide.

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Cognitive Dysfunction in Children with Heart Disease: The Role of Anesthesia and Sedation. May 2016

This article provides a detailed review of the latest research in rodents, non-human primates, and human subjects on the neurotoxic effects of early exposure to anesthesia. The authors conclude that, for the vulnerable population of children with congenital heart disease, there is a lack of definitive information to guide clinical practice.

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Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions. April 2016

Using rat embryos, researchers explore the effect of different ketamine doses on cell proliferation in the ventricular (VZ) and sub-ventricular zones (SVZ) of the brain’s cortex. Findings show reductions in cells to be dose dependent, particularly in the sub-ventricular zones.

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SafeTots responds to the release of secondary outcomes of the GAS Trial. April 2016

In their Lancet correspondence, SAFETOTS representatives praise the GAS Study interim report as the first and only prospective RCT to find no long-term neurocognitive impairment in children exposed to regional or general anesthesia, and for acknowledging the role of quality care as a possible factor. The authors call for definition of safe perioperative conduct and research on the pharmacokinetics/pharmacodynamics of frequently used anesthetics.

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Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome. April 2016

In this anesthesia database and medical record review, scientists find a significant relationship between increased cumulative hours of exposure to volatile anesthetic agents (VAA)– desflurane, halothane, isoflurane, and sevoflurane—and lower full-scale IQ and verbal IQ scores for four and five-year-olds with HLHS, a congenital heart defect.

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Xenon depresses aEEG background voltage activity whilst maintaining cardiovascular stability in sedated healthy newborn pigs. April 2016

Scientists study EEGs of five newborn pigs given one hour of IV fentanyl followed by 24 hours of ventilation with 50% xenon, 30% oxygen, and 20% nitrogen. While heart rate and blood pressure remain stable throughout the observation period, there is a significant depression in EEG ranges shortly after initiating ventilation with xenon.

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rno-miR-665 targets BCL2L1 (Bcl-xl) and increases vulnerability to propofol in developing astrocytes.  April 2016

This in-vivo rodent study finds rno-miR-665 antigomer infusion improves neurological outcomes of pups receiving propofol during early neurodevelopment. Rno-miR-665 is susceptible to propofol by negatively targeting antiapoptotic BCL2L1 and is a potential target for alternative therapeutics in pediatric anesthesia.

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The mitochondrial division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity.  March 2016

In neuron cultures from rats, researchers observe that sevoflurane or desflurane for one hour inhibits neuron development, effects mitochondria, and compromises synaptic proteins. Pretreating neurons with a mitochondrial division inhibitor (Mdivi-1) protects the mitochondria against anesthesia-induced structural and functional neurotoxicity.

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A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia. March 2016

Findings show no significant differences between children exposed to one hour or more of general anesthesia at ages 0 to 24 months and the control group for performance accuracy, response time, and brain activation patterns in the prefrontal cortex and caudate nucleus. Some differences in brain activation are observed in the cerebellum, cingulate gyrus, and paracentral lobule.

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Eat for a Cause

On Monday, May 23rd we encourage IARS Annual Meeting attendees to support SmartTots by dining at 398 Brasserie. The nearby restaurant, serving European-American fare for breakfast, lunch and dinner, has agreed to donate 5% of the day’s proceeds to support SmartTots important research.

2016 PANDA SymposiumpandaStudyLogo

Immense thanks to Dr. Lena Sun and her team! The recent PANDA Symposium provided an excellent update regarding pre-clinical and clinical pediatric neurotoxicity studies and an in-depth discussion of the way forward.


The SmartTots 2015 Annual Report is now available online!

Check it out for a complete, concise overview of our numerous accomplishments during 2015! The year saw a dynamic update of our website, the release of a new Consensus Statement and much more! Go to:

Turn your 2015 Tax refund into a 2016 Tax deduction!

Your contribution makes anesthesia safer for children around the world. Learn how you can help at

Call For Papers


Developmental Neurotoxicity Associated with Pediatric General Anesthesia: Preclinical Findings

The journal is organizing a special issue devoted to capturing the current status of the science including information on the effects of specific agents, doses, durations and frequencies of general anesthesia that occur during critical periods of brain development. The intention of this issue is to capture recent observations from well-controlled studies in animal models, and to review and synthesize these findings into a definitive description of the state of the science today. To learn more go to:

Look for us in 2016 at the following events:

IARS Annual Meeting & International Science Symposium, May 21st – 24th, 2016, San Francisco, CA

Society for Pediatric Anesthesia 30th Annual Meeting, October 21st, 2016, Chicago, IL

Society for Neuroscience in Anesthesiology and Critical Care, 44th Annual Meeting, October 20th – 21st, 2016, Chicago, IL

American Society of Anesthesiologists, Anesthesiology 2016! October 22nd – 26th, 2016, Chicago, IL

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity, June 8 – 10, 2017, Genoa, Italy

newsletter2015_2017euroStarConferenceResearch News & Updates

The Society for Pediatric Sedation recently published an item about the SmartTots Consensus Statement on the Use of Anesthetic Drugs in Infants and Toddlers in their Winter 2016 newsletter.

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Paediatric anaesthesia and neurotoxicity: can we translate findings from animals to humans? April 2016

A commentary on the importance of continuing studies in both animals and humans, despite any current shortcomings, in an effort to answer the many questions surrounding the effect of anesthesia on children’s brains and long-term neurodevelopment.

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Oral Clefts and Academic Performance in Adolescence: The Impact of Anesthesia-Related Neurotoxicity, Timing of Surgery, and Type of Oral Clefts April 2016

A Danish study of 558 children with early exposure to general anesthesia for cleft surgery looks at their 9th grade exam scores. Against the control, teens with cleft lip only (CL) scored higher while those with cleft lip and palate (CLP) scored lower—not significantly. Teens with cleft palate only (CP) scored significantly lower. Type of oral cleft rather than timing or number of surgeries associates with performance.

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SmartTots responds to the release of secondary outcomes of the GAS Trial. April 2016

Doctors representing SmartTots comment on the limitations of the secondary endpoint analysis–cognitive performance at two years–of the GAS trial. While no difference due to anesthesia exposure is a welcome observation, it is too early to draw definitive conclusions. Waiting for the more comprehensive analysis at the five-year-point is critical.

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Multiple sevoflurane exposures in infant monkeys do not impact the mother-infant bond. March-April 2016

A long-term study compares two groups of baby monkeys: one given three doses of sevoflurane for four hours; the other separated from their mothers for equivalent amounts of time. Findings immediately after sevoflurane or separation and at 24 hours post-anesthesia show no difference in the mother-infant bond between the two groups.

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Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain. March 2016

Seven-day-old rat pups exposed six times for 90 minutes show ketamine-induced cell degeneration and death in the brain’s limbic regions, but no significant changes in primary sensory regions. Similar dexmedetomidine exposure shows cell degeneration and death in primary sensory regions only.

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Lithium Protects Against Anesthesia Neurotoxicity in the Infant Primate Brain. March 2016

A study with six infant macaques (monkeys) finds that lithium, when given with isoflurane, prevents acute isoflurane–induced brain cell death and protects the oligodendroglia (the layer surrounding nerve cells in the brain) from damage.

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Preterm Versus Term Children: Analysis of Sedation/Anesthesia Adverse Events and Longitudinal Risk. March 2016

A prospective observational study with 57,227 children ages 0 to 22 years shows those born pre-term at less than 37 weeks have a nearly two-fold rate of adverse events due to non-operating-room anesthesia administration when compared to those born full term.

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Concern grows around anesthesia effects on babies – UVM Medical Center leads the world in using spinal anesthesia for surgery on babies amid growing concerns general anesthesia might adversely affect young brain development. March 2016

The article, with comments from SmartTots, highlights controversy surrounding the effect of general anesthesia on infant brains. UVM Medical Center gets the spotlight for their success with and support for spinal anesthesia in operations of less than 90 minutes on infants and children. Keeping babies awake during surgery is a plus.

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Potential neurotoxicity of anesthetic drugs in young children: who cares? A survey among European anesthetists. March 2016

A web-based survey of European anesthetists shows that a majority believe neurotoxicity in pediatric anesthesia is an important issue; it affects the way they practice. For future research, prospective human longitudinal studies focusing on neurodevelopment are their highest priority; animal studies are the lowest.

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A lasting effect of postnatal sevoflurane anesthesia on the composition of NMDA receptor subunits in rat prefrontal cortex. March 2016

Using six-day-old rats, scientists examine the effect of 2.1% sevoflurane for three days on NMDA receptors—critical for thinking and memory. Tests in postnatal days 21-35 show that sevoflurane interferes with the composition of receptors, causes hyper-locomotion and impaired memory.

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Neuronal apoptosis may not contribute to the long-term cognitive dysfunction induced by a brief exposure to 2% sevoflurane in developing rats. March 2016

Researchers assess cell death in the frontal cortex and hippocampus of baby rats administered 2% sevoflurane for three hours vs. 3% sevoflurane for six hours.  Findings show more significant long-term cognitive dysfunction in the subjects exposed for the longer duration.

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Isoflurane Is More Deleterious to Developing Brain Than Desflurane: The Role of the Akt/GSK3β Signaling Pathway. February 2016

Researchers compare the neurotoxic effects of isoflurane and desflurane, administered with lithium, on postnatal mice. Findings reveal isoflurane is more likely than desflurane to cause problems in spatial learning and memory, and aberrant expression/activation in the brain’s signaling pathways.

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A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research. January 2016

From 943 articles, researchers glean 47 pre-clinical studies in animals for systematic review. Can the methodologies in these studies help to guide human trials? Unfortunately, no, too many differing methodologies complicate the comparison between studies; relevance to human trials is still uncertain.

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What lessons for clinical practice can be learned from systematic reviews of animal studies? The case of anesthetic neurotoxicity. January 2016

While commending Disma and coworkers for key findings in the systematic review of animal studies, the authors say that even thorough reviews and meta-analyses of animal studies are inadequate as a means to guide future clinical trials. Animal studies need to be looked at individually for results that apply to humans.

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The role of TNF-α in regulating ketamine-induced hippocampal neurotoxicity. December 2015

Using brain cells in neonatal mice, researchers find that silencing TNF-α, a protein associated with inflammation and cell death, can reduce anesthesia-related neurotoxicity and improve memory function. Further, suppressing TNF-α can increase phosphorylation, a process important for healthy connections in brain pathways.

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Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor. November 2015

This retrospective study includes 20 baby monkeys: ten exposed to three, four-hour doses of sevoflurane versus ten separated from their mothers for brief periods. Results of the emotional reactivity test at six months show the group exposed to sevoflurane with significantly higher anxiety behaviors.

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Potential Adverse Effects of Prolonged Sevoflurane Exposure on Developing Monkey Brain: From Abnormal Lipid Metabolism to Neuronal Damage. October 2015

What is the effect of 2.5% sevoflurane for nine hours on the brains of infant monkeys? In tests of frontal brain tissues (DNA microarray, lipidomic and Luminex Protein analyses, Fluoro-Jade C staining), researchers observe abnormalities in gene expression, cytokine levels, and lipid metabolism as well as neuron damage.

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The uncomfortable reality…We simply do not know if general anesthesia negatively impacts the neurocognitive development of our small children. September 2015

The authors point out pros and cons of animal research, while emphasizing problems in comparing animal to human brain development. They highlight four studies in children and call for more preclinical studies on exposure to pain and general anesthesia; more prospective human trials; and a better definition of learning disabilities.

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Pediatric Anesthesia-Concerns About Neurotoxicity. June 2015

Given the lack of definitive science about the neurotoxicity of drugs used in pediatric dentistry, this Editor-in-Chief urges colleagues to take prudent steps.  Avoid drugs suspected of being neurotoxic; use regional agents with or without nitrous oxide and drugs considered less toxic, like midazolam or dexmedetomidine; limit anesthesia exposure and doses; and delay surgery until the child is older when possible.

Read More


It’s never too early to start your 2016 giving.  Why not begin with your 2015 tax return?

Your contribution makes anesthesia safer for children around the world. Learn how you can help at

The SmartTots 2015 Annual Report is now available online!

Check it out for a complete, concise overview of our numerous accomplishments during 2015! The year saw a dynamic update of our website, the release of a new Consensus Statement and much more! Go to:

Look for us in 2016 at the following events:


SmartTots Panel at the IARS Annual Meeting, Sunday, May 22nd, 2016, 10:30 – 12:00pm

SPA-AAP Pediatric Anesthesiology April 1st  3rd, 2016, Colorado Spring, CO
PANDA Symposium, April 16th  17th, 2016 New York, NY
Society for Pediatric Anesthesia 30th Annual Meeting, October 21st, 2016, Chicago, IL
Society for Neuroscience in Anesthesiology and Critical Care, 44th Annual Meeting, October 20th  21st, 2016, Chicago, IL
American Society of Anesthesiologists – Anesthesiology 2016! October 22nd  26th, 2016, Chicago, IL

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity, June 8 – 10, 2017, Genoa, Italy


Research News & Updates

Ensuring safe anaesthesia for neonates, infants and young children: what really matters, February 2016

Authors say factors affecting long-term brain health and neurocognition in children—other than anesthesia type—require attention; they call for improvements throughout the pediatric anesthesia community: better training and more experience among clinicians, standardized fellowships and clinical guidelines, improvements in dose titration

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Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia, January 2016

Are children with Complex I (CI) deficiency in brain cell respiration (brain energy) more prone to anesthesia-induced brain damage? Researchers find isoflurane has a positive rather than negative effect on the supply of energy to the brain in CI-deficient, post-natal mice.

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Acute and Long-Term Effects of Brief Sevoflurane Anesthesia During the Early Postnatal Period in Rats, January 2016

Study reveals isoflurane causes small changes in synaptic plasticity (which supports learning and memory) and dendritic spine density (associated with memory and mental agility), but no long-term disruption in brain circuits (which allow different regions of the brain to connect and process information in a coordinated way).

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α-Lipoic acid inhibits sevoflurane-induced neuronal apoptosis through PI3K/Akt signalling pathway, January 2016

Study with baby rats shows that a-Lipoic acid, an antioxidant found in all cells, reduces brain cell death in the hippocampus and subsequent cognitive impairment associated with sevoflurane administration.

Read More

Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants, January 2016

Researchers working with pre-term human neonates urge caution with midazolam doses given findings that higher doses are associated with abnormal changes in the brain’s hippocampus and lower cognitive scores.

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Differential Suppression of Spontaneous and Noxious-evoked Somatosensory Cortical Activity by Isoflurane in the Neonatal Rat, January 2016

Study with rats at postnatal ages seven to 30 days measures reactions to noxious stimuli (pain) in the cerebral cortex while under varying levels of isoflurane; finds reactions age dependent with cortical-evoked potentials (a measure of the brain’s response to pain) more resistant to isoflurane in young rats.

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Etomidate exposure in early infant mice does not induce apoptosis or affect behavior, January 2016

Using a mouse model that correlates to early infant behavior in humans, researchers look at the effect of etomidate, ketamine, and propofol on cell death in the cerebral cortex. In conclusion, none of these agents caused cell death, as measured by activated caspase-3 (a protein that plays a role in cell death) concentrations.

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The rise and fall of anaesthesia-related neurotoxicity and the immature developing human brain, January 2016

Authors believe studies in rodents and non-human primates provide the wrong roadmap for clinical care and research in pediatric anesthesia; that emerging findings from robust prospective randomized trials in humans–such as the multi-center GAS Study–are more appropriate and promising for anesthesia and its impact on brain health in children.

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Morphological features of the neonatal brain following exposure to regional anesthesia during labor and delivery, February 2015

Using MRI, researchers study brains of 37 healthy human babies, less than six weeks, exposed to regional anesthesia during labor and delivery. Infants show larger occipital and frontal lobes, and larger brain folds, than 13 babies in the control group. More studies needed to see if larger size correlates with long-term neurobehavioral problems.

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Straight Talk MD’s Dr. Frank Sweeny and Dr. Paul Yost address the question “Does general anesthesia have any long-term effects on learning, memory, or behavior in infants and children?”

Dr. Paul Yost, the Past President of the California Society of Anesthesiologists, joins host Dr. Frank Sweeny on a recent podcast that allays concerns while raising awareness for the need for more research during a discussion of the latest scientific evidence on neurocognitive effects of general anesthesia on infants and children.

Listen Here


SmartTots needs your help!

If you’ve been following the latest scientific research, you know that the animal studies indicate that certain common anesthetic and sedation drugs appear to harm the developing brain. SmartTots is accelerating efforts to fund research to identify and lessen the risks for children.

Learn how you can help at

SmartTots Featured at Anesthesiology 2015

Dr. Andrew Davidson facilitated a session entitled Anesthesiology Clinical Trials where he gave an update on selected high-profile clinical trials, all accepted for publication in Anesthesiology. The session also revealed the two year findings of the international, multi-site GAS study.

Researchers active in this area presented Neurotoxicity in the Developing Brain: An Update for the Practitioner

Special thank you to ASA and SPA for their generous support at their 2015 conferences!

SmartTots would like to extend a special thank you to the American Society of Anesthesiologists and the Society for Pediatric Anesthesia for providing SmartTots with complimentary booth space at their annual meetings. We are very grateful for the ongoing support from affiliated organizations and their members.

Look for us in 2016 at the following events:

iars_annual_meeting_2016SmartTots Panel at the IARS Annual Meeting,

Sunday, May 22nd, 2016, 10:30 – 12:00pm

  • SPA-AAP Pediatric Anesthesiology April 2016, Colorado Spring, CO
  • PANDA Symposium, April, 2016 New York, NY
  • Society for Pediatric Anesthesia 30th Annual Meeting, October 2016, Chicago, IL
  • Society for Neuroscience in Anesthesiology and Critical Care, 44th Annual Meeting, October 2016, Chicago, IL
  • American Society of Anesthesiologists – Anesthesiology 2016! October 2016, Chicago, IL

newsletter2015_2017euroStarConferenceSave the Date:

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity,

June 8 – 10, 2017, Genoa, Italy

Research News & Updates

The following seven items represent related abstracts presented at the American Society of Anesthesiologists Conference, Anesthesiology 2015:

Latent Class Analysis of Neuropsychological (NP) Deficit After Exposure to Anesthesia in Early Childhood, October 2015

Study of 1444 children associates less severe neuropsychological (NP) deficits with early exposure to anesthesia; severe NP deficits lack the association. Risk factors other than early exposure to anesthesia may lead to severe NP deficits. Read More

Identifying Children at Risk for Anesthetic Neurotoxicity, October 2015

Retrospective cohort study finds one in seven children, given sevoflurane at less than three years of age, at risk for neurotoxicity. Read More

Dexmedetomidine Mitigates Neuroapoptosis Induced by Prenatal Intravenous Anesthetic Exposure in Rats, October 2015

Animal study finds that giving pregnant rats dexmedetomidine, a sedative, prior to propofol and ketamine helps reduce anesthesia-related cell damage in fetal brain tissue. Read More

Development of a Translational, Preclinical Piglet Model of Anesthesia-Induced Neurotoxicity Mechanisms in the Pediatric Population, October 2015

Researchers present a piglet model as ideal way to study impact of anesthesia on neuroinflammation and improve anesthesia safety for children. This model is less costly than other animal models and may prove superior in moving promising findings from the bench to preclinical phases of testing. Read More

Neuroinflammation and Ischemic Neurodegeneration in the Central Nervous System of Newborn Piglets After Isoflurane Anesthesia, October 2015

Study of brains in baby pigs given isoflurane and lipopolysaccharide (LPS) reveals deadly effect these agents have on developing cells in the cortex and hippocampus, along with their potential to block the flow of blood and oxygen to the brain. Read More

Estimation and Analysis of Unnecessarily Early Procedures in Infants Younger than Six Month of Age in the United States, October 2015

Analysis finds more than 8,500 unnecessary surgical procedures per year in the U.S. on infants less than six months. Higher rates occur in certain states and to families with private insurance or no insurance more so than to those in government-sponsored health plans. Read More

Neonatal MRI: Can We Reduce Anesthesia Exposure? A National Survey, October 2015

Survey of all U.S. NICUs (with 60% response rate) concludes that, for MRI of the brain in neonates, the first-line method for keeping the baby motionless should be the feed and swallow technique (FS) versus use of sedation and general anesthesia (GA). Read More

A Less Risky Anesthesia for Babies, December 2015

The author discusses ongoing research efforts aimed at clarifying the benefits and risks, including impairments in cognitive function, of spinal anesthesia over general anesthesia for infants and toddlers undergoing surgery. Spinal anesthesia is proving successful for certain types of surgeries, but doctors await results of new studies on long-term effects. Read More

Information, Communication Lacking for Neurotoxicity in Pediatric Anesthesia, December 2015

Results of a survey from Children’s Hospital of Philadelphia to leaders in the anesthesia community reveals a widespread lack of consistency in the approach to managing anesthesia-related toxicity in children, calls for more education to clinicians, professionals, and parents on the state of the science. Read More

Anesthesia-Induced Neuronal Apoptosis in the Developing Retina: A Window of Opportunity, November 2015

Using MRI technology, researchers observe cell death in the retinas of rats exposed to isoflurane. Findings offer a promising, non-invasive approach for measuring the neurotoxicity of isoflurane in the brains of infants and children. Read More

Steven Roth, MD, Department of Anesthesiology, University of Illinois, responds in an Editorial.

Dr. Roth commends Cheng and colleagues for advancing a non-invasive method for seeing the toxic effect of isoflurane on cells in the retina of rats; a method that, one day, may help scientists study the effect of anesthesia on human brain cells in real time. Read More

Negotiating the dilemma of anaesthesia and sedation in NICUs, October 2015

The author highlights a lack of clinical guidelines for prolonged use of anesthesia and sedation in neonates. He encourages further interpretation of findings from the Europain Study, which he believes will translate into practice improvements and better patient safety. Read More

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial, October 2015

Using the Bayley Scales (a standard series of measurements used to assess motor, language, and cognitive development of infants and toddlers), researchers find the secondary outcome, a composite cognitive score, in the GAS trial. They report no significant difference in mean scores for children assessed at age two who received less than one hour of sevoflurane versus awake-regional anesthesia for a hernia repair. Read More

Long-Term Behavioral Effects in a Rat Model of Prolonged Postnatal Morphine Exposure, October 2015

Newborn rats given morphine show less tolerance to heat stimulation in stress tests when compared to rats given saline only. This hypersensitivity to heat for newborns on morphine is associated with an increased sensitivity to pain in adulthood. Read More

Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study, October 2015

A study of 6680 neonates in 243 NICUs within 18 European countries shows a wide variation in sedation practices and a need for more research.  Scientists assessed pain, drug withdrawal syndromes, and the association between tracheal ventilation, exposure to opioids, sedative-hypnotics, and general anesthesia. Read More

General Anesthesia in Peds May Affect Brain Development and IQ Scores, September 2015

The author addresses questions that remain about the effects of general and regional anesthesia on the child’s brain. She highlights research and commentary from Dr. Andreas Loepke at Cincinnati Children’s; Dr. Andrew Davidson at Melbourne Children’s Trials Center; and Dr. Geoff Fawley at Royal Children’s in Melbourne. Read More

Neonatal anesthesia: how we manage our most vulnerable patients, September 2015

This review defines the unique challenges for high-risk neonates undergoing surgical procedures and anesthesia exposure.  The authors call for greater sensitivity to the needs of these babies and meticulous medical management in an effort to improve overall outcomes. Read More

Pediatric dental sedation: challenges and opportunities, August 2015

Some sedation in children’s dental procedures has led to death and impairment, including permanent brain damage.  The authors explore sedation agents and methods currently in use and on the horizon that promise greater safety with less toxicity and trauma to the patient. Read More

Efficacy of rutin in inhibiting neuronal apoptosis and cognitive disturbances in sevoflurane or propofol exposed neonatal mice, August 2015

Research with baby rats finds that combining rutin, a natural substance in plants and foods, with sevoflurane and propofol administration reduces the toxic effects of these drugs on brain cells, including those associated with memory and cognition. Read More

Anesthetic use in newborn infants: the urgent need for rigorous evaluation, July 2015

Authors highlight the need for more research and clinical guidance on the safety, toxicity, and effectiveness of drugs used as anesthesia and analgesia on neonates and infants.  There have been few drug label updates for newborns and none for premature infants; “off-label” drugs frequently used in this population require more testing. Read More

Age-dependency of sevoflurane-induced electroencephalogram dynamics in children, July 2015

How EEG patterns, measuring electrical activity in the brain, go up and down in children exposed to general anesthesia is not well understood.  Researchers observe alpha wave coherence–a correlation of EEG signals at different scalp locations–to be high in adults, but absent in one-year olds under sevoflurane, revealing its variable effect by age on developing brain circuits. Read More

Long-term action of propofol on cognitive function and hippocampal neuroapoptosis in neonatal rats, July 2015 

Study shows low doses of propofol to be safe during early brain growth in baby rats, but repeated mid to high doses can lead to cell death, inflammation, and impaired cognitive function. Read More

Neuroprotective properties of vitamin C on equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in high fat diet fed neonatal mice, July 2015

Researchers, working with normal weight and obese baby mice, find that administering vitamin C along with desflurane, isoflurane or sevoflurane reduces the toxic effects of these agents by protecting against brain cell death and reducing impairments in memory and learning. Read More

Propofol: A Review of its Role in Pediatric Anesthesia and Sedation, July 2015

Use of propofol in children needing sedation is common, but this drug is currently off-label for children, meaning it lacks guidelines for use with pediatric patients.  In this review, the authors discuss the pros and cons of propofol use in children, vis-à-vis side effects, complications, and neurotoxicity. Read More

Surgical Anesthesia in Young Children Linked to Effects on IQ, Brain Structure, June 2015

A retrospective study from Cincinnati Children’s finds children exposed to general anesthesia score five to six points lower in listening comprehension and performance IQ, which may translate to a lifetime in lost wages.  For the 6 million children in the U.S. who undergo surgery every year, this is a lifetime potential earnings loss of $540 billion. Read More

Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants, June 2015

Observational study examines brain wave oscillations using multi-electrode EEG and “multitaper spectral methods” with infants on sevoflurane; finds decrease in theta and alpha brain waves as infants four to six months emerge from surgery and sevoflurane level goes down.  More sensitive brain monitoring methods, like this, may offer new strategies for lowering anesthesia risk in children. Read More

The Anesthesia Dilemma: Researchers are trying to determine if chemicals used to knock out young children during surgery can have long-term repercussions on memory and development, June 2015

Recent animal studies find general anesthesia harmful to brain development, cognition, and memory, but measuring the degree of deficit in humans is difficult; variables other than anesthesia exposure may be at play.  The author describes new studies and video games with children that may offer insight into the link between anesthesia and cognitive deficits. Read More

SmartTots wishes all of our subscribers a happy and healthy 2016!

2015 Archive


If you’ve been following the latest scientific research, you know that the animal studies indicate that certain common anesthetic and sedation drugs appear to harm the developing brain. SmartTots is accelerating efforts to fund research to identify and lessen the risks for children.

Learn how you can help at

Consensus Statement on the use of Anesthetic and Sedative Drugs in Infants and Toddlers

Join us for the Second EuroSTAR – SmartTots Scientific Conference:  Pediatric Anesthesia and Neurotoxicity, June 8 – 10, 2017, Genoa, Italy 

Research News & Updates 

Recent Study Shows No Difference between General Anesthesia and Regional Anesthesia in Short Duration Surgery, October 2015

GAS study researchers release report describing the secondary outcome of cognitive performance at 2 years of age based on 532 subjects. Read More

SmartTots responds to the release of the GAS Study results with a Supplement to the Consensus Statement.  Read More

microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes, June 2015

Our results shed light on the anesthetic mechanism of propofol and have implications for its use in the clinical setting. Read More

Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy, June 2015

There is a particular need to examine the impact of the choice of spinal over general anaesthesia on respiratory and neurological outcomes in high-risk infant subgroups with severe respiratory disease and previous brain injury. Read More

Cognition and Brain Structure Following Early Childhood Surgery With Anesthesia, June 2015

The present findings suggest that general anesthesia for a surgical procedure in early childhood may be associated with long-term diminution of language abilities and cognition, as well as regional volumetric alterations in brain structure. Read More

Joshua J Davis, Medical Student at Sidney Kimmel Medical College, Thomas Jefferson University responds in a letter to the editor. Read More

Thomas Engelhardt, Pediatric Anesthesiologist, Department of Anaesthesia, Royal Aberdeen Children’s Hospital responds in a letter to the editor. Read More

Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells, June 2015

Quantitative analysis shows that the number of differentiated neurons was substantially reduced in 10μM ketamine-exposed cultures in differentiation medium, compared with the controls. Read More

Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum, June 2015

Exposure of immature rats to general anesthesia during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum. Read More

Long-term NMDA receptor inhibition affects NMDA receptor expression and alters glutamatergic activity in developing rat hippocampal neurons, June 2015

Long-term blockade of the NMDA receptor in developing rat hippocampal neurons significantly increased NR1 subunit expression, and that this was associated with an alteration in neuronal activity. Read More

Safe Anesthesia For Every Tot – The SAFETOTS initiative, June 2015

The improvement of teaching, training, education and supervision of the safe conduct of pediatric anesthesia are the main goals of the initiative. Read More

Is this your (paediatric patient’s) brain on (anaesthetic) drugs?: The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans, May 2015

Given the immense importance for individual wellbeing as well as societal health, intensified research efforts are needed to determine whether or not surgical procedures with general anaesthesia have any long-term effects on the developing human brain. Read More

Risk of autistic disorder after exposure to general anaesthesia and surgery: A nationwide, retrospective matched cohort study, May 2015

Exposure to general anaesthesia and surgery before the age of 2 years age at first exposure and number of exposures were not associated with the development of autistic disorder. Read More

Carbon monoxide modulates Cytochrome Oxidase Activity and Oxidative Stress in the Developing Murine Brain During Isoflurane Exposure, May 2015

Carbon monoxide-mediated effects could have implications for the development of low-flow anesthesia in infants and children in order to prevent anesthesia-induced oxidative stress. Read More

Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, A Randomized Controlled Trial, May 2015

RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Read More

Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, May 2015

Awake regional anesthesia is a viable alternative to general anesthesia for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. Read More

Elevation of Sestrin-2 expression attenuates Sevoflurane induced neurotoxicity, May 2015

These results suggest that the suppressive effects of Sestrin-2 on neuroapoptosis against the Sevoflurane anesthesia in neuronal cells might be associated with modulation of mitochondrial pathway. Read More

Impact of propofol anaesthesia on cytokine expression profiles in the developing rat brain: A randomised placebo-controlled experimental in-vivo study, May 2015

This study suggests that propofol anaesthesia does not have a major impact on pro-inflammatory cytokine expression profiles in the developing central nervous system during the brain growth spurt. Read More

Regional anaesthesia in neonates, infants and children: An educational review European Journal of Anaesthesiology, May 2015

Performing regional blocks in anaesthetised children is a safe and generally accepted practice. Read More

Anesthesia and the developing brain: a way forward for clinical research, May 2015

It may be impossible to conduct a single study to exclude the possibility that anesthetics can produce long-term neurobehavioural changes in humans; however, observational studies will improve our understanding of which children are at greatest risk, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome. Read More

Dexmedetomidine Attenuates Neurotoxicity Induced by Prenatal Propofol Exposure, April 2015

Dexmedetomidine attenuates neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring rats. Read More

Perioperative effects of caudal and transversus abdominis plane (TAP) blocks for children undergoing urologic robot-assisted laparoscopic surgery, April 2015

Administration of caudal blocks should be considered for children of suitable age undergoing RAL surgery involving either the upper or lower urinary tract. Read More

Only extra-high dose of ketamine affects l-glutamate-induced intracellular Ca2+ elevation and neurotoxicity, April 2015

Long-term exposure to TPS or ketamine at clinical doses during developmental periods may not result in a dose-related potentiation of exogenous glutamate-induced neurotoxicity, once the intravenous anesthetics are discontinued. Read More

Developmental stage-dependent impact of midazolam on calbindin, calretinin and parvalbumin expression in the immature rat medial prefrontal cortex during the brain growth spurt, April 2015

These data provide us with one potential mechanism that could account for the lasting neurobehavioral and cognitive deficits observed in the context of anesthesia exposure in the early postnatal period. Read More

Neurotoxicity of Generic Anesthesia Agents in Infants and Children: An Orphan Research Question in Search of a Sponsor, April 2015

More studies and trials are needed to address questions about the optimal dose, duration, and frequency of use of anesthetic agents and vulnerable periods of exposure in young children. Read More

Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats, April 2015

A subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. Read More

Neurodevelopmental implications of the general anesthesia in neonate and infants, April 2015

In this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies. Read More

Repeated Exposure to Ketamine-Xylazine during Early Development Impairs Motor Learning-dependent Dendritic Spine Plasticity in Adulthood, April 2015

Our study demonstrates that repeated exposures to ketamine-xylazine during early development impair motor learning and learning-dependent dendritic spine plasticity later in life. Read More

Safety and feasibility of xenon as an adjuvant to sevoflurane anaesthesia in children undergoing interventional or diagnostic cardiac catheterization: study protocol for a randomised controlled trial, March 2015

Xenon provides remarkable haemodynamic stability and potentially has cardio- and neuroprotective properties. Unfortunately, evidence is scarce on the use of xenon in the paediatric population. Read More

Anesthetic-Related Neurotoxicity in Children – ASA Works in Close Cooperation With FDA and Others to Advance Research, March 2015

Based on their latest approach to investigating and funding studies of anesthetic neurotoxicity, SmartTots and the FDA have been increasingly determined to position the research to hone in on the question of whether the increased risk of cognitive deficits seen in some studies is truly a result of the anesthetic medications or due to another reason entirely. Read More

Interventional Procedures for Chronic Pain in Children and Adolescents: A Review of the Current Evidence, March 2015

The potential for severe complications resulting from interventional procedures in the treatment of chronic pain for children and adolescents leaves open a debate on the safety of these procedures, which must be confirmed by more extensive and accurate prospective studies. Read More

Special aspects of pediatric anesthesia in ophthalmic surgery, February 2015

In animal experiments it could be proven that neuronal apoptosis could be induced by most of the commonly used anesthetics. It has not yet been clarified whether this has an effect on the neurocognitive development of children. There is, however, widespread agreement that a necessary anesthesia carried out in a correct and controlled manner has no negative consequences for children. Read More

Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study, February 2015

Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Read More

Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice, January 2015

Curcumin pre-administration can prevent the sevoflurane exposure-induced cognitive impairment later in life, which may be partly attributed to its ability to attenuate the neural apoptosis, inflammation, and oxidative nitrosative stress in mouse brain. Read More

Single sevoflurane exposure increases methyl-CpG island binding protein 2 phosphorylation in the hippocampus of developing mice, January 2015

Sevoflurane causes neurotoxicity in the developing brain. This neurotoxicity can be prevented by the N-methyl-D-aspartate glutamate receptor inhibitor memantine. Read More

Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure, January 2015

These findings suggest a “threshold effect for general anesthetic-induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss. Read More


Latest Updates from the IARS Annual Meeting, March 21-24, Honolulu, HI

Video Presentation Neurotoxicity of Anesthetics in the Developing Brain – A Translational Update Recorded live on March 23 at the IARS Annual Meeting in Honolulu, HI. Panelists: Ansgar Brambrink, MD, PhD; Andreas W. Loepke, MD, PhD; Vesna Jevtovic-Todorovic, MD, PhD, MBA; Andrew Davidson, MBBS, MD, FANZCA

SmartTots-Related Abstract Judged Best of Meeting Academic Performance After Anesthesia and Surgery During Childhood: A Large-Scale Nation-Wide Study Pia Glatz, MD, R. H. Sandin, N. L. Pedersen, A. E. Bonamy, L. I. Eriksson, F. N. Granath

Research News & Updates

Anesthetic neurotoxicity–clinical implications of animal models. The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age. Read more

Neurodevelopment of children exposed to anesthesia: Design of the Mayo Anesthesia Safety in Kids (MASK) study The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks. Read more

Is There Evidence for Long-Term Neurocognitive Effects of Sedatives Given the public health implications of anesthetic and sedative drugs on the developing brain, this chapter will discuss relevance of these issues in the context of the management of sedation in pediatric patients undergoing diagnostic and painful procedures.  Read more

A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia fMRI appears to be a useful tool in evaluating the long-term effects of early exposure to general anesthesia. Read more

Dexamethasone but not the equivalent doses of hydrocortisone induces neurotoxicity in neonatal rat brain. Hydrocortisone is probably safer to use than dexamethasone in the immediate postnatal period in neonatal rats. Cautious extrapolation of these findings to human premature infants is required. Read more

Altered Metabolomic Profiles May Be Associated with Sevoflurane-Induced Neurotoxicity in Neonatal Rats. Our data indicate that sevoflurane anesthesia causes significant oxidative stress, neuroapoptosis, and cellular ultrastructure damage, which is associated with altered brain metabotype in the neonatal rat. Read more

Hyperexcitability of Rat Thalamocortical Networks after Exposure to General Anesthesia during Brain Development Drugs that regulate thalamic excitability may improve the safety of GAs used during early brain development.  Read more

Repeated Exposure to Ketamine-Xylazine during Early Development Impairs Motor Learning-dependent Dendritic Spine Plasticity in Adulthood Repeated exposures to ketamine-xylazine during early development impair motor learning and learning-dependent dendritic spine plasticity later in life. Read more

Neuroprotective effects of pterostilbene against isoflurane-induced apoptosis through regulating the JNK and PI3K/Akt pathway in neonatal rats Observations suggest that pterostilbene was able to effectively reduce isoflurane-induced neurodegeneration. Read more

Effect of apoptosis in neural stem cells treated with sevoflurane Sevoflurane can inhibit the central nervous system by activating γ-Aminobutyric acid (GABA) is a known inhibitory neurotransmitter in central nervous system.  The result is apoptosis of neural stem cells, thus leading to the NSCs degeneration. Read more

Molecular pathways of mitochondrial dysfunctions: Possible cause of cell death in anesthesia-induced developmental neurotoxicity. The molecular processes of mitochondrial dysfunction should be understood to develop novel therapeutic strategies that can prevent anesthesia-induced neurotoxicity and provide neuroprotection against developmental central nervous system. Read more

Propofol inhibits proliferation and induces neuroapoptosis of hippocampal neurons in vitro via downregulation of NF-κB p65 and Bcl-2 and upregulation of caspase-3 These results indicated that downregulation of NF-κB p65 and Bcl-2 likely led to the caspase-3 activation, triggered apoptosis and inhibited the neuronal growth and proliferation that we have observed in our in vitro systems. Read more

Pre-treatment with a Xingnaojing preparation ameliorates sevoflurane-induced neuroapoptosis in the infant rat striatum. These data suggest that the standardized Chinese herbal medicine XNJ has an antiapoptotic effect against sevofluraneinduced cell loss in the striatum. It thus holds promise as a safe and effective neuroprotective agent. Read more

Safety and feasibility of xenon as an adjuvant to sevoflurane anaesthesia in children undergoing interventional or diagnostic cardiac catheterization: study protocol for a randomised controlled trial. Read More

2014 Archive


Research News & Updates

FDA Science Board Meets

The FDA Science Board met on November 19 to review the existing nonclinical and clinical data related to the use and potential toxicity of anesthetics and sedation drugs in the pediatric population.

Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children. 

This paper reviews some of the preclinical background behind anesthesia-related neurotoxicity but focuses mainly on the human studies. It concludes that the human studies performed so far have been unable to confirm the animal data. A single brief anesthetic seems safe in infants. Multiple anesthetic and surgical exposures on the other hand are different, but this may be due to reasons other than the anesthetics.  Read more

Are Caudal Blocks for Pain Control Safe in Children? An Analysis of 18,650 Caudal Blocks from the Pediatric Regional Anesthesia Network (PRAN) Database.

Safety concerns should not be a barrier to the use of caudal blocks in children assuming an appropriate selection of local anesthetic dosage.  Read more

Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice.

These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3β activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice.  Read more

Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment

These results suggest that Vitamin C attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels.  Read more

Ketamine Affects the Neurogenesis of Rat Fetal Neural Stem Progenitor Cells via the PI3K/Akt-p27 Signaling Pathway.

The inhibition of PI3K/Akt-p27 signaling may be involved in ketamine-induced neurotoxicity in the developing brain, whereas excitatory NMDA receptor activation may reverse these effects.  Read more



FDA Science Board Review: November 19

On November 19, 2014, the FDA Science Board will review the existing nonclinical and clinical data related to the use and potential toxicity of anesthetics and sedation drugs in the pediatric population. 

Consensus Statement and Revision

In December 2012, SmartTots released a Consensus Statement on the Use of Anesthetics and Sedatives in Children to provide guidance to healthcare providers and parents with regard to research findings that suggest anesthetics may be harmful to the developing brain. Consideration of the emerging evidence has prompted a revision of the 2012 statement.  Read more

Research News & Updates

Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study

Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, pooling of major/minor conditions and major/minor surgeries should be avoided.  Read more

Do we actually need to anesthetize the neonate?

Recurring themes are that neonatal physiology is substantially different from older children, that there are substantial gaps in our understanding of basic pharmacology and physiology, and there is a relative paucity of strong clinical evidence to guide practice.  Read more

Report of the Fourth PANDA Symposium on Anesthesia and Neurodevelopment in Children

The PANDA symposium has become a platform to review current preclinical and clinical data related to anesthetic neurotoxicity, to discuss relevant considerations in study design and approaches to future research among clinicians and researchers, and finally to engage key stakeholders in this controversial public health topic.  Read more

Clinical Research Into Anesthetic Neurotoxicity: Does Anesthesia Cause Neurological Abnormalities in Humans?

Additional preclinical and clinical research efforts are urgently required to address the effects of anesthetic exposure in human brain development.  Read more

Review: effects of anesthetics on brain circuit formation

There is evidence that anesthetics can disrupt brain circuit formation, including effects on neuronal survival and neurogenesis, neurite growth and guidance, formation of synapses, and function of supporting cells.  Read more

Isoflurane Impairs the Capacity of Astrocytes to Support Neuronal Development in a Mouse Dissociated Coculture Model

Isoflurane interferes with the ability of cultured astrocytes to support neuronal growth. This finding represents a potentially novel mechanism through which general anesthetics may interfere with brain development.  Read more

Postoperative Cognitive Function Following General Versus Regional Anesthesia: A Systematic Review

Sixteen studies were included in the final analysis. Three studies showed some difference in cognitive function between regional and general anesthesia, whereas the remaining 13 showed no difference between regional and general anesthesia on postoperative cognitive function.  Read more

Neurodevelopmental Outcomes After Initial Childhood Anesthetic Exposure Between Ages 3 and 10 Years

Decreased motor function was found in children initially exposed after age 3 even after accounting for comorbid illness and injury history.  Read more

Engaging Stakeholders in Research Related to Anesthesia and Neurodevelopment in Children

Clinicians and researchers need to adopt strategies to engage and partner with stakeholders as co-investigators who actively participate in efforts to increase anesthetic safety in children.  Read more

Pediatric Surgeons and Anesthesiologists Expand the Dialogue on the Neurotoxicity Question, Rationale for Early and Delayed Surge

Given recent publications suggesting the potential for neurotoxicity following anesthesia in pediatric patients, physicians, parents, and other stakeholders are now challenged to continue to balance safety with efficacy in caring for children. Read more


Research News & Updates

Cognitive Outcome after Spinal Anesthesia and Surgery During Infancy

Our study found no link between duration of surgery with infant spinal anesthesia (SA) and scores on academic achievement testing in elementary school. We also found no relationship between infant SA and surgery with very poor academic achievement (VPAA) on elementary school testing, although the confidence intervals (CIs) were wide. Read more

Cognitive Outcomes After Infant Spinal Anesthesia: The Other Side of the Coin

In their study, Williams etal. have provided us with aglimpse at thepreviouslyunseen flip sideof the anesthesia-surgerycoin assessing whether asurgicalprocedure maycontribute to adversecognitive outcome laterinchildhood. Read more

Neonatal Anesthesia Neurotoxicity: A Review for Cleft and Craniofacial Surgeons

The timing and number of cleft and craniofacial surgeries in our treatment protocols may need to be reevaluated to account for these potential risks. Read more

Erythropoietin protects newborn rat against sevoflurane-induced neurotoxicity

Six hours of sevoflurane anesthesia in newborn rats induces significant long-term cognitive impairment. A single administration of rh-EPO immediately after postnatal exposure to sevoflurane reduces both early activation of apoptotic phenomenon and late onset of neurologic disorders.  Read more

Isoflurane impairs the capacity of astrocytes to support neuronal development in a mouse dissociated coculture model.

Isoflurane interferes with the ability of cultured astrocytes to support neuronal growth. This finding represents a potentially novel mechanism through which general anesthetics may interfere with brain development. Read more

Role of miR-34c in ketamine-induced neurotoxicity in neonatal mice hippocampus

Cognitive examination with the Morris water maze test showed that ketamine-induced memory impairment was significantly improved by miR-34c downregulation.Read more

Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. Read more


SmartTots Featured at Canadian Anesthesiologists’ Society Annual Meeting 2014

SmartTots would like to extend a special thank-you to the Canadian Anesthesiologists’ Society, for providing SmartTots with complimentary booth space at the their annual meeting in St. John’s, Newfoundland.  We are grateful for the continued support from our affiliated organizations and their members.

Research News & Updates

Long term neurotoxicity by general anesthetics in infants

A large volume of literature has accumulated in the form of animal and human studies which have implicated general anesthetic drugs like ketamine, propofol, volatile agents, and benzodiazepines in the development of neurodegenerative conditions in later life.  A direct cause effect relationship is yet to be firmly established.  Further research and evidence in this arena is demanded. Read more

Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell-derived Neurons.

These data suggest that (1) human embryonic stem cell-derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in human embryonic stem cell-derived neurons, and (3) the propofol-induced cell death may occur via a signal transducer and activator of transcription 3/miR-21/Sprouty 2-dependent mechanism. Read more

Anesthetic Preconditioning Inhibits Isoflurane-Mediated Apoptosis in the Developing Rat Brain

The ISO-mediated increase in cleaved caspase-3 in the postnatal day 7 rat brain is ameliorated by preconditioning with a brief anesthetic exposure, and differences were not detected in other markers of neuronal injury. Read more

Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats.

Our results indicate that the JNK and p38 pathways, not the ERK pathway, are involved in dexmedetomidine-induced neuroprotection against isoflurane effects. Read more

Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain.

Ketamine caused neuroapoptosis and impaired brain functions in the developing rat brain, which can be effectively attenuated by dexmedetomidine. Dexmedetomidine alone was not neurotoxic to the developing brain. Read more

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats.

Propofol-caused acute increases in corticosterone levels and γ-aminobutyric acid type A receptor-mediated excitation at the time of anesthesia may play mechanistic roles in development of exacerbated endocrine responses to stress and neurobehavioral abnormalities. Read more

Comparison of neurodegeneration and cognitive impairment in neonatal mice exposed to propofol or isoflurane.

Both isoflurane and propofol caused significant apoptosis in the mouse developing brain, with isoflurane being more potent. Isoflurane significantly increased levels of the plasma neurodegenerative biomarker, S100β. However, these neurodegenerative effects of isoflurane and propofol in the developing brain were not associated with effects on inflammation or with cognitive dysfunction in later life. Read more

Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1α Pathway in Developing Rats.

We suggest that ketamine-induced neurodegeneration in neonatal rats, followed by long-term cognitive deficits, might be mediated via the ROS/HIF-1α pathway. Read more

Impact of ketamine on learning and memory function, neuronal apoptosis and its potential association with miR-214 and PTEN in adolescent rats.

Ketamine at a dose of 80 mg/kg in the adolescent rats is able to induce the learning and memory impairment and neurodegeneration, in which the down-regulation of miR-214 and high expression of PTEN protein may be involved. Read more


Successful SmartTots Workshop Held in Washington, DC

A highly productive SmartTots Workshop was held in Washington, DC on June 20.  More than 50 researchers and stakeholders convened to identify a study or series of studies that would inform the future scientific direction and fundraising activities of the SmartTots initiative, and to consider whether modifications to the 2012 Consensus Statement on the Use of Anesthetics and Sedatives in Children are warranted in light of the additional research findings over the past 18 months.  Significant progress was made toward both objectives. The workshop commenced with a charge from the SmartTots Steering Committee Co-Chairs, Dr. Santhanam Suresh of Lurie Children’s Hospital in Chicago and Dr. Bob Rappaport, Director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA Center for Drug Evaluation and Research, followed by presentations from 11 investigators who reported on their studies and findings to date.  The participants then split into two breakout sessions, with one discussing the needed studies while the other considered the Consensus Statement.  The group reconvened in a plenary session to hear reports from the breakout groups and discuss their work. A complete report on the workshop outcomes will be included in a future SmartTots e-Newsletter.

Research News & Updates

Effect of General Anesthesia in Infancy on Long-Term Recognition Memory in Humans and Rats Twenty eight children ages 6-11 who had undergone a procedure requiring general anesthesia before age 1 were compared to 28 age- and gender-matched children who had not undergone anesthesia.  In parallel, thirty-three 7-day-old rats were randomized to receive anesthesia or sham anesthesia.  Our findings suggest that general anesthesia in infancy impairs recollection later in life in humans and rats. In rats, this effect is independent of underlying disease or tissue injury. Read more

General anaesthetics and the developing brain: an overview. Anaesthetic exposure during a critical period of neuronal development can have significant impact on neurocognitive function later in life. Until proven otherwise, it can be recommended to keep anaesthesia and surgery as short as possible, to use short-acting drugs and/or a combination of general anaesthesia and multimodal pain therapy including systemic analgesics, and local or regional anaesthesia, to reduce the overall drug dosage.  Read more

The Neonatologist’s Role in Pediatric Anesthesia Neurotoxicity A fundamental assumption of anesthetic practice has always been that the effects of sedatives and anesthetic agents resolve when these drugs are metabolized and excreted from the body. This core assumption has recently been challenged by compelling evidence in animals. In this context, we welcome the publication by Morriss et al in this issue of the journal. However, as is true with every human neurotoxicity study to date, their work raises as many questions as it answers. Read more

Cognitive Outcome after Spinal Anesthesia and Surgery During Infancy Our study found no link between duration of surgery with infant spinal anesthesia (SA) and scores on academic achievement testing in elementary school. We also found no relationship between infant SA and surgery with very poor academic achievement (VPAA) on elementary school testing, although the confidence intervals (CIs) were wide. Read more

Repeated Exposure to Anesthetic Ketamine Can Negatively Impact Neurodevelopment in Infants: A Prospective Preliminary Clinical Study.

Our results suggest that 3 or more exposures to anesthetic ketamine have the potential to adversely affect neurodevelopment in infants.  Read more

The role of miR-21 in propofol-induced neurotoxicity in developing human neurons (1093.2)

In this study, we assessed the effects of propofol on human embryonic stem cell (hESC)-derived neurons and the role of microRNAs (miRs) in the toxicity observed. hESCs were differentiated into neurons following a four-step differentiation protocol. Exposure to 20 µg/mL propofol for 6 hours induced significant cell death in the hESC-derived neurons and downregulated several microRNAs, including miR-21. Overexpression of miR-21 significantly attenuated the increase in cell death following propofol administration. Read more

Inhibition of aberrant cyclin-dependent kinase 5 activity attenuates isoflurane neurotoxicity in the developing brain

Our results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain. Read more

Involvement of RAGE in isoflurane-induced neuronal apoptosis

Isoflurane has been reported to cause neurotoxicity and neurocognitive impairments in neonatal rats. Previous reports suggest elevated levels of S100B after anesthesia and brain trauma. The receptor for advanced glycation end products (RAGE) is the only known cell surface receptor for S100B and expressed in the brain. RAGE activation in neurons has also been shown to lead to apoptosis and neurodegeneration. Our research demonstrates that RAGE may be involved in the neuronal apoptosis induced by isoflurane. Read more

The role of miR-124 in modulating hippocampal neurotoxicity induced by ketamine anesthesia

Our study demonstrated that miR-124 played an important role in regulating ketamine induced hippocampal neurodegeneration. Inhibiting miR-124 may provide a molecular target to improve memory performance in both human and animals suffering from over-anesthetic related neurotoxicity. Read more

Sevoflurane in combination with propofol, not thiopental, induces a more robust neuroapoptosis than sevoflurane alone in the neonatal mouse brain

Sevoflurane alone can induce neuronal apoptosis, and this effect is enhanced by propofol. Thiopental did not exacerbate the neurotoxicity of sevoflurane. There is the possibility that the combination of sevoflurane and propofol is a more harmful anesthetic technique than sevoflurane alone in pediatric patients. Read More

Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring.

Data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits.Read more

Propofol anesthesia induces proapoptotic tumor necrosis factor-α and pro-nerve growth factor signaling and prosurvival Akt and XIAP expression in neonatal rat brain

These results show that different brain structures respond to propofol anesthesia with a time- and duration-of-exposure-dependent increase in proapoptotic signaling and with concomitant increases in activities of prosurvival proteins. We hypothesized that the fine balance between these opposing processes sustains homeostasis in the immature rat brain and prevents unnecessary damage after exposure to an injurious stimulus. The existence of this highly regulated process provides a time frame for potential therapeutic intervention directed toward suppressing the deleterious component of propofol anesthesia. Read more

SmartTots Workshop

Friday, June 20, 2014: Sheraton Crystal City Hotel, Washington, DC

Open to all interested professionals. No registration fee.

Workshop Agenda:

  • Updates on the ongoing studies, including results to date
  • Additional studies needed to answer the questions about the potential neurotoxicity of anesthetics in the developing human brain
  • Dealing with the uncertainties about anesthetics and children in the practice environment
  • Does the Consensus Statement on the Use of Anesthetics and Sedatives in Children need revision?
  • Raising the funds required to conduct the needed studies

May 2014

Mark your calendar!

SmartTots Workshop

Friday, June 20, 2014: Crystal City Marriott at Reagan National Airport, Washington, DC

Open to all interested professionals. No registration fee.

Workshop Objectives:

  1. Develop a shared understanding of the recent and ongoing studies regarding pediatric anesthesia neurotoxicity, including rationale, study design, and results to date.
  2. Determine what additional studies are needed, including study design and cost.
  3. Identify strategies for a proposal to government sources to raise the funds required to conduct the needed studies.

Please contact Rebekah Davies, IARS Program Manager for more information or to register for the workshop. [email protected]   415-296-6905

Research News & Updates

Comparative Analysis of Outcome Measures Used in Examining Neurodevelopmental Effects of Early Childhood Anesthesia Exposure

When assessing cognition in children with early exposure to anesthesia, the results may depend on the outcome measure used. Neuropsychological and International Classification of Diseases, 9th Revision, Clinical Modification-coded clinical outcomes showed an increased risk of deficit in exposed children compared with that in unexposed children, whereas academic achievement scores did not. This may explain some of the variation in the literature and underscores the importance of the outcome measures when interpreting studies of cognitive function.  Read more

The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. 

After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12 months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes.  Read more

Anesthetic neurotoxicity

This article provides an overview of the currently available data from both animal experiments and human clinical studies regarding the effects of sedatives and anesthetics on the developing brain.  Read more

Anesthesia and the Developing Brain: Relevance to the Pediatric Cardiac Surgery

Children potentially at greater risk for anesthetic neurotoxicity, based on a prolonged anesthetic exposure early in development, are those receiving anesthesia for surgical repair of congenital heart disease. These children not only receive prolonged anesthetic exposure during surgical repair but also repeated anesthetic exposures during a critical period of brain development. Their propensity to abnormal brain development, as a result of congenital heart disease, may modify their risk of anesthetic neurotoxicity. This review article provides insight into basic science and clinical investigations as it relates to this unique group of children.  Read more

Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.  Read more

Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. We summarize laboratory data published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function, and we discuss findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.  Read more

Basic aspects of the potential toxicity of anesthetic drugs

During the last decade, numerous in vitro and in vivo experimental studies in newborn animal models have established the neurotoxic effects of most anesthetic and sedative drugs used in pediatrics.  These data are insufficient to change our practices, however progress in experimental research will help us identify the safest therapeutic strategies and neuroprotective treatments.   Read more

Subclinical Carbon Monoxide Limits Apoptosis in the Developing Brain After Isoflurane Exposure

It is possible that low-flow anesthesia designed to target rebreathing of specific concentrations of CO may be a desired strategy to develop in the future in an effort to prevent anesthesia-induced neurotoxicity in infants and children.  Read more

Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains

The underlying mechanism by which dexmedetomidine reduces neuronal injury during a prolonged anesthesia remains unclear. In this study, we compare the neurotoxic effects of dexmedetomidine and ketamine, a general anesthetic with a different mechanism of action, in fetal cynomolgus monkeys.  In utero treatment with ketamine resulted in marked apoptosis and degeneration primarily in layers I and II of the frontal cortex. In contrast, fetal brains from animals treated with dexmedetomidine showed none to minimal neuroapoptotic or neurodegenerative lesions at both low- and high-dose treatments.  Read more

Dexmedetomidine Reduces Isoflurane-Induced Neuroapoptosis Partly by Preserving P13K/Akt Pathway in the Hippocampus of Neonatal Rats

Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, causes neurodegeneration in the developing animal brains. Recent studies showed that dexmedetomidine, a selective α2-adrenergic agonist, reduced isoflurane-induced cognitive impairment and neuroapoptosis. The mechanisms for the effect are not completely clear.  Our results suggest that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.  Read more

Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females

There is mounting evidence that children exposed to anesthetic agents sustain lasting effects on learning and memory. Rodent models have shown that isoflurane exposure in newborns induces acute neuroapoptosis and long-term cognitive impairment.  In our study on male and female Sprague Dawley rats, we found that isoflurane exposure significantly increased neuronal death in each brain region with no difference between sexes. However, only males were impaired in the recognition of objects in different locations and contexts. Males also exhibited deficient social memory while females were intact.  Read more

Exposure to general anesthesia in early life and the risk of attention deficit/hyperactivity disorder development: a nationwide, retrospective matched-cohort study

Exposure to general anesthesia before 3 years of age was not associated with ADHD.  Read more

Neuroprotective gases–fantasy or reality for clinical use?

In this review, we summarize the literature concerning the neuroprotective effect of each gas and its underlying mechanisms, extract common targets reported for the neuroprotective effects of different gases, highlight the conflicting observations from clinical trials and further discuss the possible hindrances impeding clinical applications in order to propose future research perspectives and therapeutic exploitations.  Read more

Neonatal Morphine in Extremely and Very Preterm Neonates: Its Effect on the Developing Brain, a Review

Preterm infants requiring intensive care experience procedures requiring management of stress and pain. This overview of research on the use of morphine and its neurodevelopmental effects on neonates finds no definite conclusions concerning the effects of neonatal morphine on long term neurodevelopmental outcomes. More prospectively designed trials should be conducted using reliable and validated pain assessment scores to evaluate effects of morphine on long term neurodevelopmental outcomes in preterm infants.  Read more


March 2014

Mark your calendar!

SmartTots Workshop

Friday, June 20, 2014: Sheraton Crystal City Hotel, Washington, DC

Open to all interested professionals. No registration fee.

Workshop Agenda:

  • Updates on the ongoing studies, including results to date
  • Additional studies needed to answer the questions about the potential neurotoxicity of anesthetics in the developing human brain
  • Dealing with the uncertainties about anesthetics and children in the practice environment
  • Does the Consensus Statement on the Use of Anesthetics and Sedatives in Children need revision?
  • Raising the funds required to conduct the needed studies

Please contact Rebekah Davies, IARS Program Manager for more information or to register for the workshop. [email protected]   415-296-6915

Research News & Updates

Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children?

A review of presently available evidence regarding anesthesia-induced neurocognitive and social behavioral impairments and possible strategies for preventing them, and of limited and somewhat controversial evidence that examines the effects of nociception and surgical stimulation on anesthesia–induced developmental neurotoxicity. Read more

 Anesthesia considerations in pediatric glaucoma management

As the potential long-term adverse neurodevelopmental effects of general anesthesia become better understood, pediatric glaucoma specialists should be cognizant of the relative lifelong risks and benefits of repeat examinations under anesthesia in young patients. Read more

 Adverse effect of inhalational anesthetics on the developing brain

Experimental studies using animal models have indicated some adverse effect of anesthetics, especially neurotoxicity, in the developing brain.  More evidence is needed before a recommendation can be made to change the way those anesthetics are used in the pediatric population. Two clinical trials underway may provide insight to the potential human neurotoxic effect of anesthetics. Read more

 Dual effects of ketamine: neurotoxicity versus neuroprotection in anesthesia for the developing brain

Ketamine is widely used in pediatric anesthesia.  Animal studies have shown that ketamine may have neurotoxic effects on the developing brain.  Other studies have shown ketamine protects the central nervous system by inhibiting inflammation in the developing brain.  Balancing the neurotoxic and neuroprotective effects of ketamine on the developing brain may be possible, but further study is required. Read more

 Isoflurane-induced Apoptosis of Neurons and Oligodendrocytes in the Fetal Rhesus Macaque Brain

Isoflurane anesthesia for 5 hours causes death of neurons and oligodendrocytes in the G120 fetal NHP brain. In the fetal brain, as the authors previously found in the neonatal NHP brain, oligodendrocytes become vulnerable when they are just achieving myelination competence. The neurotoxic potential of isoflurane increases between the third trimester (G120) and the neonatal period in the NHP brain. Read more

 Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the developing brain.

Sedation and anesthesia are often necessary for children at any age, and are frequently provided in ambulatory settings. Concerns have mounted, based on both laboratory studies including various mammalian species and retrospective human clinical studies, that the very drugs that induce sedation and anesthesia may trigger an injury in the developing brain, resulting in long-lasting neurobehavioral consequences. Read more

 The potential dual effects of sevoflurane on AKT/GSK3beta signaling pathway.

Anesthetic sevoflurane might induce a dual effect (increase versus decrease) on the activation of the AKT/GSK3beta signaling pathway. These studies have established a system to perform further studies to determine the effects of sevoflurane on brain function. Read more

 Physiological disturbance may contribute to neurodegeneration induced by isoflurane or sevoflurane in 14 day old rats.

Volatile anesthetics are widely used in pediatric anesthesia but their potential neurotoxicity raise significant concerns regarding sequelae after anesthesia.  These findings could suggest physiological disturbance induced by isoflurane or sevoflurane anesthesia may also contribute to their neurotoxicity. Read more

 Early life exposure to sevoflurane impairs adulthood spatial memory in the rat.

Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit. Read more

Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study.

Young age at anesthetic exposure is believed to be critical, but human studies are scarce. This study found children operated for pyloric stenosis (PS) before 3 months of age have educational performance tests similar to the background population at age 15-16 years after adjusting for known confounders. The higher nonattainment rate could suggest that a subgroup of PS children is developmentally disadvantaged. Read more

 Modeling anesthetic developmental neurotoxicity using human stem cells.

Development of an in vitro neurogenesis system using human stem cells has opened up avenues of research for advancing our understanding of human brain development and the issues relevant to anesthetic-induced developmental toxicity in human neuronal lineages. Read more

2013 Archive


SmartTots Featured at Anesthesiology 2013

Special thank you to ASA, SNACC, and SPA! SmartTots would like to extend a special thank-you to the American Society of Anesthesiologists, the Society for Neuroscience in Anesthesiology and Critical Care, and the Society for Pediatric Anesthesia for providing SmartTots with complimentary booth space at the their annual meetings in San Francisco this month. We continue to receive much support from affiliated organizations and its members.

Research News & Updates

A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses. Concern has been expressed that infants and children exposed to uneventful surgery and anesthesia may incur neurological injury that becomes manifest in poor scholastic performance or future learning difficulties. A recent meta-analysis of seven clinical studies examined the relationship between learning or behavior difficulties and pediatric exposure to anesthesia/surgery and reported an odds ratio of 1.4; however, the level of association and causal factors remain unclear. The purpose of our study is to provide context to the pediatric anesthesia neurotoxicity question by reviewing the evidence linking four childhood illnesses with neurocognitive development. In the present review, we have sought to quantify the magnitude of the impact of chronic illness on neurocognitive development through a systematic review of publications that report the developmental trajectory of patients with four childhood diseases: cystic fibrosis (CF), hemophilia A, end-stage renal disease (ESRD) and end-stage liver disease (ESLD). Read more

Neurotoxicity of general anesthetics in childhood: does anesthesia leave its mark on premature babies, newborns and infants? Many animal experiments have shown that anesthetics can have a neurotoxic effect on immature brains because they induce apoptosis and influence neurogenesis and synaptogenesis. In animal experiments this has substantial implications for the neurocognitive functions of animals in later life. Whether these results of animal experiments can be transferred to humans is currently the subject of intensive research. In several retrospective studies no clear association between anesthesia in premature babies, newborns or infants and the occurrence of learning disorders or behavioral problems could be found.  Read more


SmartTots Funds $400,000 for Pediatric Anesthesia Research

SmartTots is dedicated to funding research that will help determine if any particular anesthetic or sedative drugs pose hazards to young children, design the safest anesthetic and sedative regimes, and potentially foster the development of new practice guidelines and anesthetic drugs. In support of this goal, two research grants for $200,000 each paid over two years were recently awarded to: Dr. Lena Sun, Columbia University Medical Center in support of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Study Dr. Jeffrey Sall, University of California San Francisco in support ofRecognition Memory Following Early Childhood Anesthesia Click here to view the full media release regarding the 2013/2014 grant awardees.

Research News & Updates

FDA Consumer Update Released: Anesthesia: Is it Safe for Young Brains? When infants or young children need surgery, does anesthesia affect their developing brains? With more than 1 million children under age 4 requiring anesthesia for surgery in the United States each year, the Food and Drug Administration (FDA) and other health organizations are working together to answer this question. Read more

Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss Volatile anesthetics are widely used in the clinic, and sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia. Recent findings question the potential risks of volatile anesthetics on brain development. Evidence suggests that sevoflurane may cause neuronal deficiency. This study investigates the long-term effect of sevoflurane in the developing brain. Read more

Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain Exposure of the fetal or neonatal non-human primate (NHP) brain to isoflurane or ketamine for 5 h causes widespread apoptotic degeneration of neurones, and exposure to isoflurane also causes apoptotic degeneration of oligodendrocytes (OLs). The present study explored the apoptogenic potential of propofol in the fetal and neonatal NHP brain. Read more

Ketamine as anesthetics can damage children’s learning and memory ability Recent studies have found that anesthesia drugs have neurotoxicity on the developing neurons, causing learning and memory disorders and behavioral abnormalities. Ketamine is commonly used in pediatric anesthesia. A clinical retrospective study found that children below 3 years old who receive a long time surgery, or because of surgery require ketamine repeatedly will exhibit the performance of school-age learning and memory disorders and behavioral abnormalities. Read more

Characterization and Quantification of Isoflurane-Induced Developmental Apoptotic Cell Death in Mouse Cerebral Cortex Accumulating evidence indicates that isoflurane and other, similarly acting anesthetics exert neurotoxic effects in neonatal animals. However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized. We conducted the present study to immunohistochemically identify the dying cells and to quantify the fraction of cells undergoing apoptotic death in neonatal mouse cortex, a substantially affected brain region.Read more


Now Accepting Applications: SmartTots 2013 Research Grants

SmartTots is now accepting applications aimed at investigating whether anesthetics/sedatives are neurotoxic and/or impede the normal development of the human brain. Projects should focus on whether neonatal anesthetic exposure in humans impairs brain development resulting in persistent detrimental effects on cognition or behavior. Studies aimed at identifying either specific anesthetic techniques that do not produce neurotoxic effects or interventions to ameliorate damage will also be considered. Deadline to apply is April 12, 2013. Get started on your application.

IARS 2013 Annual Meeting

The IARS 2013 Annual Meeting in San Diego (May 4-7) will include three panels on the safety and potential impact of pediatric anesthesia.

  • SmartTots Panel: Update on New Scientific Advances in Anesthetic Neurotoxicity in the Developing Brain
  • ISAP Panel: The Best of the New in Clinical Pharmacology
  • APSF Panel: General Anesthesia for Infants Having Surgery and Elective Procedures: Is it Safe?

Don’t miss the 2013 Party with a Purpose fundraiser, which will raise funds for SmartTots research. Purchase your ticket by April 15th to be entered to win an Apple iPad Mini.

Recent Literature

Anesthetics Interfere with Axon Guidance in Developing Mouse Neocortical Neurons In Vitro via a γ-Aminobutyric Acid Type A Receptor Mechanism The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity. Read more

Dual Effects of Isoflurane on Proliferation, Differentiation, and Survival in Human Neuroprogenitor Cells Previous studies have demonstrated that isoflurane can provide both neuroprotection and neurotoxicity in various tissue culture models and in rodent developing brains. The cellular and molecular mechanisms mediating these dual effects are not clear, but the exposure level and duration of isoflurane appear to be determinant factors. Read more

Prognostic Study of Sevoflurane-Based General Anesthesia on Cognitive Function in Children It is unclear whether volatile general anesthetics have sustained adverse effects on the immature brains of children. The authors performed a self-controlled study to evaluate the effects of strabismus surgery under sevoflurane-based general anesthesia on the cognitive function of pediatric patients. Read more


Request for Applications Update

SmartTots will begin accepting applications for its second round of research grants in early February. Two $200,000 grants will be available. View the preliminary RFA.

Recent Literature

Sevoflurane Anesthesia in Pregnant Mice Induces Neurotoxicity in Fetal and Offspring Mice

Each year, over 75,000 pregnant women in the United States undergo anesthesia care. The authors set out to assess the effects of the anesthetic sevoflurane on neurotoxicity in pregnant mice and on learning and memory in fetal and offspring mice. Read more

Early Developmental Exposure to Volatile Anesthetics Causes Behavioral Defects in Caenorhabditis elegans

The authors hypothesized that exposing the nematode (C. elegans) to volatile anesthetics early in life would induce neuron cell death, producing a behavioral defect that would be manifested in adulthood. Read more

Selective Anesthesia-induced Neuroinflammation in Developing Mouse Brain and Cognitive Impairment

The authors have established an animal model with single versus multiple exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different types of anesthesia in cognitive impairment. Read more

Repeated Exposure to Propofol Potentiates Neuroapoptosis and Long-term Behavioral Deficits in Neonatal Rats

The authors investigated the effects of neonatal propofol anesthesia on neuroapoptosis and long-term spatial learning/memory functions. Read more

2012 Archive

October 2012

Experts Work Towards Developing Consensus Regarding Anesthetic Safety in Children

Although the anesthesia community and the FDA agree there are insufficient data to demonstrate a causal link between the use of anesthetics and neurotoxicity in the human pediatric population, the need has grown to communicate accurately to practitioners and parents the current understanding of the risks. On September 10, 2012, the International Anesthesia Research Society (IARS) and the U.S. Food and Drug Administration (FDA) held a SmartTots Scientific Workshop with the goal of developing a consensus statement regarding the safety of anesthetic and sedative drugs administered to infants and young children. Over 60 experts in pediatric medicine and patient safety attended. Read More

Recent Research Articles

SmartTots: A Public-Private Partnership Between the United States Food and Drug Administration (FDA) and the International Anesthesia Research Society (IARS)

A history of the SmartTots public-private partnership between the IARS and FDA is presented. SmartTots was established to raise money for research to better understand the relationship between sedative and anesthetic agents and neurotoxicity in the developing brain. Read More

Propofol at Clinically Relevant Concentrations Increases Neuronal Differentiation But Is Not Toxic to Hippocampal Neural Precursor Cells In Vitro

Propofol in the early postnatal period has been shown to cause brain cell death. One proposed mechanism for cognitive dysfunction after anesthesia is alteration of neural stem cell function and neurogenesis. The authors examined the effect of propofol on neural precursor or stem cells (NPCs) grown in vitro. Read More

General Anesthesia: A Gateway to Modulate Synapse Formation and Neural Plasticity?

Appropriate balance between excitatory and inhibitory neural activity patterns is of utmost importance in the maintenance of neuronal homeostasis. General anesthetic–induced pharmacological interference with this equilibrium results not only in a temporary loss of consciousness but can also initiate long-term changes in brain function. Read More

Anesthetics and the Developing Brain: Time for a Change in Practice? A Pro/Con Debate

Early clinical observations, approximately 60 years ago, raised the possibility of a causal link between anesthesia exposure and CNS dysfunction in young children. However, this issue only gained widespread interest following the publication of experimental data less than 15 years ago. Read More

Upcoming Events

Society for Pediatric Anesthesia’s 2012 International Assembly for Pediatric Anesthesia

October 11-12, 2012, Washington, DC Related Sessions

  • Keynote: IARS Lecture – SmartTots
  • Anesthetics and the Developing Brain: Time for a Change in Practice?

Visit SmartTots at Booth 20!

SNACC 40th Anniversary Annual Meeting

October 11-12, 2012, Washington, DC Related Sessions

  • Poster Session: Neurotoxicity 1

Visit SmartTots at Booth 4!

American Society of Anesthesiologists’ Anesthesiology 2012

October 13-17, 2012, Washington, DC Related Sessions

Visit SmartTots in Concourse A!

American Academy of Pediatrics National Conference & Exhibition

October 20-23, 2012, New Orleans, LA Related Sessions

Visit the SmartTots booth at the Surgical Reception following the Joint Surgery Conference!

September 2012

SmartTots-Funded Research Projects

SmartTots is pleased to announce Robert Block, PhD and Caleb Ing, MD as the recipients of our inaugural round of research grants. Dr. Block and Dr. Ing are investigating the existence of a clinical signal suggesting poor neurocognitive outcomes as the result of early exposure to anesthesia. Both recipients received $100,000 to fund their studies. Read More

CaleIngb Ing, MD Columbia University Anesthetic Exposure Duration and Effects on Cognitive and Language Ability Block photographRobert Block, PhD University of Iowa General Anesthesia During Human Infancy and Brain Development IARS Awards $750,000 Grant to Investigate Effect of Anesthetics in Non-Human Primates (NHPs) IARS awarded Ansgar Brambrink, MD, PhD, of Oregon Health & Science University, with a $750,000 research grant to investigate long-term consequences of anesthesia exposure in infant non-human primates (NHPs), an experimental model with high translational relevance to the human condition. Dr. Brambrink’s studies will determine whether negative consequences occur in non-human primates, which should bring the scientific and medical communities closer to translating the animal data to humans. Read More Brambrink1Ansgar Brambrink, MD, PhD Oregon Health & Science University Long-Term Outcome of Single vs. Triple Anesthesia Exposure of Infant Monkeys

Special Thanks!

The Japan Society for Clinical Anesthesia Donates $20,000!

The Japan Society for Clinical Anesthesia (JSCA) has demonstrated its commitment and support of the SmartTots Initiative with a donation of $20,000 for pediatric anesthesia research. Read More

Over $17,000 Raised for SmartTots Research at the IARS 2012 Annual Meeting!

Thank you to all who attended the 2012 Party with a Purpose fundraiser, held at this year’s IARS Annual Meeting in Boston, on May 20, 2012. The event hosted more than 140 guests and raised more than $17,000 for SmartTots research! Thanks again to the event sponsors and donors for their generous contributions! To view photos from this year’s Party with a Purpose, including Dr. Steven Shafer’s escape from a straight jacket, visit the SmartTots Facebook page!

Recent Research Articles

SmartTots Researchers Publish Separate Articles Linking Single Anesthetic Exposure to Poor Neurocognitive Outcomes in Pediatric Patients

Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood?

Clonidine Abolishes the Adverse Effects on Apoptosis and Behavior after Neonatal Ketamine Exposure in Mice

An increasing amount of both experimental and epidemiological data indicates that neonatal anesthesia causes disruption of normal brain development in rodents and primates, as manifested by acute increased apoptosis and long-lasting altered behavior and learning. It is necessary to seek strategies that avoid the possible adverse effects after anesthesia. Read More

Review Article: Neuraxial Analgesia in Neonates and Infants: A Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. Read More

Neonatal Exposure to Sevoflurane Causes Apoptosis and Reduces nNOS Protein Expression in Rat Hippocampus

A growing number of studies have shown that commonly used anesthetic agents may cause neurohistopathological changes and persistent behavioral impairments in the developing brain. The effects of sevoflurane, a widely used substance in pediatric anesthesia, on the developing brain have not been thoroughly analyzed thus far. Read More

March 2012

Current Research

Delayed environmental enrichment reverses sevoflurane-induced memory impairment

Anesthesia given to immature rodents causes cognitive decline, raising the possibility that the same might be true for millions of children undergoing surgical procedures under general anesthesia each year. The authors tested the hypothesis that anesthesia-induced cognitive decline in rats is treatable. Read more

Neurotoxicity and the need for anesthesia in the newborn: Does the emperor have no clothes?

In 2011 nearly half the pediatric papers in Anesthesiology were related to neurotoxicity of general anesthetics to the developing brain. There is continued debate about the clinical relevance of the animal data, and the interpretation of human cohort studies. As we slowly unravel the question of whether or not general anesthetics cause any clinically significant effect on brain development, we should perhaps address some wider-related issues that sometimes go unsaid. Read more

Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia

Authors study the association between exposure to procedures performed under general anesthesia before age 2 years and development of attention-deficit/hyperactivity disorder (ADHD). Read more

Effect of general anesthetics on the developing brain

Studies on rodents and subhuman primates suggest that prolonged exposure to general anesthetics may induce widespread neuronal cell death and neurological sequelae, seriously questioning the safety of pediatric anesthesia. This review presents recent developments in this rapidly emerging field. Read more

Upcoming Events

World Congress of Anesthesiologists

March 25-30, 2012,
 Buenos Aires, Argentina Related Sessions 
• Mechanisms of Perioperative Neurotoxicity • Perioperative Cognitive Dysfunction

International Anesthesia Research Society 2012 Annual Meeting

May 18-21, 2012, Boston, Massachusetts Related Sessions 
• Pediatric Anesthesia Neurotoxicity • Pediatric Anesthesia: Little People with Lots of Problems! • Developmental Neurotoxicity: Are the Narcotics Safe?

Euroanesthesia 2012

June 9-12, 2012, Paris, France Related Sessions • General Anesthesia and the Developing Brain: Is Anything Safe?

Party with a Purpose!

Join your colleagues on Sunday, May 20th as we “Party with a Purpose” at the 2012 Annual Meeting in Boston. This fundraising dinner will help raise awareness of, and funds for, anesthesia research. This exciting event includes a hosted bar (beer/wine), dinner/dessert, live music/dancing as well as an auction featuring stays in Las Vegas and Aruba! Black tie optional. Tickets are $100 each. Visit the event webpage for more information and to purchase your ticket today (advertising and sponsorship opportunities also available).

January 2012

Current Related Research

The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: The importance of free oxygen radicals and mitochondrial integrity

Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reactive oxygen species (ROS), which, if not scavenged in timely fashion, may cause excessive lipid peroxidation and damage of cellular membranes. This study examines whether early exposure to GA results in ROS upregulation and whether mitochondrial protection and ROS scavenging prevent GA-induced pathomorphological and behavioral impairments. Read More

Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain

Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus fetuses and neonates. Read More

Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation

Propofol exposure to neurons during synaptogenesis results in apoptosis, leading to cognitive dysfunction in adulthood. Previous work from the authors’ laboratory showed that isoflurane neurotoxicity occurs through p75 neurotrophin receptor (p75NTR) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75NTRRead More

Protective function of nicotinamide against ketamine-induced apoptotic neurodegeneration in the infant rat brain

During development, anesthetics activate neuroapoptosis and produce damage in the central nervous system that leads to several types of neurological disorders. A single dose of ketamine (40 mg/kg) during synaptogenesis in a 7-day-old rat brain activated the apoptotic cascade and caused extensive neuronal cell death in the forebrain. In this study, we investigated the protective effect of nicotinamide against ketamine-induced apoptotic neurodegeneration. Read More

Effects of metabotropic glutamate receptor 7 allosteric agonist N,N’-dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 Mitogen-activated protein kinase signaling pathway

The present study was designed to evaluate the possible neuroprotective effects of metabotropic glutamate receptor (mGluR7) allosteric agonist N,N’-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) on developmental sevoflurane neurotoxicity. Read More

Upcoming Events

EURO-NEURO 2012: 7th International Update on Interdisciplinary Neuroscience

February 16-18, 2012, 
Vienna, Austria Related Sessions 
• Neuroprotection and Neurotoxicity

World Congress of Anesthesiologists

March 25-30, 2012,
 Buenos Aires, Argentina Related Sessions 
• Mechanisms of Perioperative Neurotoxicity • Perioperative Cognitive Dysfunction

International Anesthesia Research Society 2012 Annual Meeting

May 18-21, 2012, Boston, Massachusetts Related Sessions 
• Pediatric Anesthesia Neurotoxicity • Pediatric Anesthesia: Little People with Lots of Problems! • Developmental Neurotoxicity: Are the Narcotics Safe?

2011 Archive

December 2011

SmartTots-Related Research Articles

Nociceptive Stimuli Enhance Anesthetic-Induced Neuroapoptosis in the Rat Developing Brain

Anesthetic-induced neurodegeneration in the developing brain has been well documented. However, the experiments carried out so far do not include surgical conditions. This proof of concept study was designed to investigate the impact of nociceptive stimuli on anesthetic induced neuroapoptosis in the rat developing brain. Read more.

Repeated Administration of Propofol Upregulated the Expression of c-Fos and Cleaved-Caspase-3 Proteins in the Developing Mouse Brain

This study was designed to analyze the relationship between the expression of c-Fos protein and apoptosis in the hippocampus following propofol administration in infant mice. No adequate evaluations have been available as to whether the dosage of propofol to maintain anesthesia could trigger the expression of c-Fos and apoptosis. Read more.

Transient Effects of Anesthetics on Dendritic Spines and Filopodia in the Living Mouse Cortex

Anesthetics are widely used to induce unconsciousness, pain relief, and immobility during surgery. It remains unclear whether the use of anesthetics has significant and long-lasting effects on synapse development and plasticity in the brain. To address this question, the authors examined the formation and elimination of dendritic spines, postsynaptic sites of excitatory synapses, in the developing mouse cortex during and after anesthetic exposure.Read more.

Ketamine and Propofol in Combination Induce Neuroapoptosis and Down-Regulate the Expression of N-Methyl-D-Aspartate Glutamate Receptor NR2B Subunit in Rat Forebrain Culture

Ketamine has always been used in combination with propofol in pediatric patients. This study aimed to investigate whether ketamine or ketamine in combination with propofol induces apoptosis and regulates the expression level of NMDA receptor NR2B subunit in rat forebrain culture. Read more.

Upcoming Events

EURO-NEURO 2012: 7th International Update on Interdisciplinary Neuroscience

February 16-18, 2012 Vienna, Austria Related Sessions • Neuroprotection and Neurotoxicity

World Congress of Anesthesiologists

March 25-30, 2012 Buenos Aires, Argentina Related Sessions • Mechanisms of Perioperative Neurotoxicity • Perioperative Cognitive Dysfunction

Give the Gift of Research

SmartTots is currently reviewing research proposals and will be awarding our first round of research grants early 2012. Show your support this holiday season by donating to the SmartTots research effort. 100% of your gift will support research and is completely tax deductible in the United States! Donate now.

November 2011

Recent SmartTots-Related Research Articles

Anesthetic Neurotoxicity: A Difficult Dragon to Slay

It has become difficult to open an anesthesiology journal without seeing an article about anesthetic neurotoxicity. Most of the work has been done in animals and suggests that harm can come to the developing brain when it is exposed to a broad array of commonly used anesthetic and sedative agents. The critical question, of course, is, does it happen in children? Read more.

The Role of Calcium Dysregulation in Anesthetic-Mediated Neurotoxicity

Increasing evidence suggests that general anesthetics, either volatile or IV, can induce cell death by apoptosis in a concentration- and time-dependent manner in different types of cells, including neurons, in various animal models. Read more.

Anesthetics and Sedatives: Toxic or Protective for the Developing Brain?

Despite our insufficient understanding of the exact molecular mechanisms of general anesthetics and sedatives, every year millions of children are treated with these drugs in a seemingly safe manner. However, increasing evidence particularly from animal studies has suggested the possibility for deleterious effects in pediatric patients. Read more.

Anesthetic-Related Neurotoxicity and the Developing Brain: Shall We Change Practice?

Accumulating experimental evidence together with recent epidemiologic observations suggest that general anesthetics might exert undesirable effects on the immature nervous system. The goal of this review is to highlight basic science issues as well as to critically present experimental data and clinical observations relevant to this possibility. Read more.

News and Events

SmartTots Featured in Anesthesia & Analgesia

The November issue of Anesthesia & Analgesia, now in circulation, highlights current research related to pediatric anesthesia neurotoxicity and the SmartTots research effort. This issue features eight articles, including an editorial from SmartTots Steering Committee Co-Chairs Drs. James Ramsay and Bob Rappaport. Read now.

European Society of Anesthesiologists Establishes European Task Force

SmartTots affiliate, the European Society of Anesthesiologists, is recruiting individuals to serve on their Euro-SmartTots Task Force. Euro-SmartTots is designed to further SmartTots research and fundraising efforts in Europe. Learn more.

World Congress of Anaesthesiologists

March 25-30, 2012 Buenos Aires, Argentina Panel Alert: Mechanisms of Perioperative Neurotoxicity

Every Donation Makes a Difference

SmartTots needs your help to assess the impact of anesthetics on the developing brain. Donate today to support the needed research and SmartTots Executive Board Chair Dr. Michael Roizen will add a matching donation. Your support will help ensure the safety of millions of infants and young children who undergo anesthesia and sedation each year.

October 2011

Recent SmartTots-Related Research

Cognitive and Behavioral Outcomes After Early Exposure to Anesthesia and Surgery

Repeated exposure to anesthesia and surgery before the age of 2 shown to be a significant independent risk factor for the later development of learning disabilities but not the need for educational interventions related to emotion/behavior. Read More

Neurotoxicity of Anesthetic Drugs in the Developing Brain

Anesthesia kills neurons in the brain of infantile animals, including primates, and causes permanent and progressive neurocognitive decline. The anesthesia community and regulatory authorities alike are concerned that is also true in humans. Read More

Neonatal Desflurane Exposure Induces More Robust Neuroapoptosis than Do Isoflurane and Sevoflurane and Impairs Working Memory

In an animal model, neonatal desflurane exposure induced more neuroapoptosis than did sevoflurane or isoflurane and impaired working memory, suggesting that desflurane is more neurotoxic than sevoflurane or isoflurane. Read More

GABAergic Excitotoxicity Injury of the Immature Hippocampal Pyramidal Neurons’ Exposure to Isoflurane

Isoflurane-mediated enhancement of GABA-triggered [Ca2+]i release results from membrane depolarization with subsequent activation of VDCCs and further Ca2+-induced Ca2+ release from the ryanodine-sensitizing Ca2+ store. Read More

General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain

Developing mitochondria are exquisitely vulnerable to general anesthesia and may be important early target of anesthesia-induced developmental neurodegeneration. Read More November issue of Anesthesia & Analgesia to feature SmartTots and pediatric anesthesia neurotoxicity. Issue mails end of October.

Coming Up

Society for Pediatric Anesthesia’s 25th Annual Meeting

October 14, 2011 Hyatt McCormick Place, Chicago, Illinois Panel Alert: Anesthesia for the Neonate – Yesterday, Today and Tomorrow: From Paralysis to Toxicity

Anesthesiology 2011 – American Society of Anesthesiologists

October 15-19, 2011 McCormick Place Complex, Chicago, Illinois Panel Alert: Anesthetic Related Neurotoxicity in Children: Research, Regulation and Practice

Request for Applications – Deadline Approaching

The last day to submit a proposal in response to our request for applications is October 21. Studies aimed at investigating whether anesthetics impede brain development are welcome. Read the full RFA and apply now.

Show Your Support

Millions of infants and young children receive anesthesia each year. Without the necessary research data, we have no way of knowing whether these children are at risk for future developmental difficulties. Your donation will help fund research needed to ensure safe anesthetic exposure. Will you show your support by donating today? 100% of your gift will be directly allocated to research, and Dr. Michael Roizen, Chair of our Executive Board, will match your donation with a personal contribution of his own.

September 2011

Safety of Anesthetics Strongly Age Dependent

General anesthesia administered to the developing animal brain depresses much needed neuronal activity and communication resulting in long-lasting cognitive impairment, according to an article published in the August issue of Current Opinion in Anesthesiology. Learn more

Dr. Michael Roizen Takes SmartTots to India

Dr. Michael Roizen, Chair of the SmartTots Executive Board, presented a key session dedicated to pediatric anesthesia neurotoxicity in Bengaluru, India on Saturday, August 27. Anesthesiologists from eight countries convened to hear Dr. Roizen discuss recent outcomes and ongoing research efforts related to the safe use of anesthetics in young children. Read more

Grants and Resources

Request for Applications

We are now accepting research proposals aimed at investigating whether anesthetics impede the normal development of the human brain. Applications accepted now through October 21. Read the full RFA and submit an application

Now Available: Speaker Presentations from Neurotoxicity Panel

Presentations from our Pediatric Anesthesia Neurotoxicity panel held at the IARS 2011 Annual Meeting in Vancouver, Canada are now available for review and download. View speaker presentations

Upcoming Events

Anesthesia for the Neonate – Yesterday, Today and Tomorrow: From Paralysis to Toxicity

October 14, 2011 Society for Pediatric Anesthesia’s 25th Annual Meeting Hyatt McCormick Place, Chicago, Illinois Speakers to discuss laboratory findings related to anesthetic-induced developmental neurotoxicity, whether these findings can be extrapolated to clinical care, and safe alternatives for anesthesia and sedation in neonates.

Anesthetic Related Neurotoxicity in Children: Research, Regulation and Practice

October 15, 2011 Anesthesiology 2011 – American Society of Anesthesiologists McCormick Place Complex, Chicago, Illinois Speakers to highlight current clinical and preclinical research suggesting anesthetic exposure may be toxic to the developing brain and potential changes in practice that may result from ongoing research and public concerns.

August 2011

Translating the animal data

Following the FDA’s Advisory Committee Meeting in March, our Scientific Advisory Board acknowledged insufficient data available to determine whether anesthetics induce neurotoxicity in the developing human brain. We are dedicating our initial research investigations to elucidating whether a clinical signal exists. See our key research questions.

Data links anesthesia & learning disabilities Infants and very young children exposed to anesthesia may experience higher rates of learning disabilities and cognitive difficulties than children who are not exposed to anesthesia according to research and emerging data presented on May 23, during our Pediatric Anesthesia Neurotoxicity panel at the IARS annual meeting in Vancouver, B.C. Read more.

Fundraising campaign in motion

The International Anesthesia Research Society just donated $200,000 and Dr. Mike Roizen committed an annual $50,000 challenge grant, launching our first fundraising campaign. 100% of all individual donations will be directly allocated to research. Will you donate today, and help us achieve Dr. Roizen’s challenge?

Recent Articles

We are committed to keeping you informed. View recent articles in anesthetic neurotoxicity research. Recently published an article or have one in the pipeline? Send us an email and we’ll keep you on our radar.

Our Supporters

We would like to thank our partners for their commitment to ensuring the safety of anesthetics in infants and young children.
American Academy of Pediatrics
Anesthesia & Analgesia
Anesthesia Patient Safety Foundation
American Society of Anesthesiologists
Canadian Anesthesiologists’ Society
International Anesthesia Research Society
Society for Neuroscience and Critical Care in Anesthesiology
Society for Pediatric Anesthesia
Society for Paediatric Anaesthesia in New Zealand and Australia
US Food and Drug Administration