SmartTots 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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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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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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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: https://www.guidestar.org/Profile/7397424. 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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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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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 SmartTots.org/donate

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: smarttots.org/resources/livestream

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.

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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.org/donate

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!

Medical research is fundamental to our health and economic prosperity!  We at SmartTots are grateful that Congress has made medical research a national priority through supporting the National Institutes of Health (NIH) and passage of the 21st Century Cures Act.  But, without sustained, predictable funding for NIH, tomorrow’s cures may never come. Join SmartTots and urge lawmakers to increase the NIH budget in FY2018 by $2 billion and provide hope to millions of Americans living with life-threatening and chronic diseases. Participate in the #RallyMedRes www.rallyformedicalresearch.org

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: smarttots.org/resources/livestream

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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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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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

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

News

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

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

March 2014

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

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

• Anesthetic Related Neurotoxicity in Young Children: An Update
• Your Patient Wants to Know Whether Anesthesia and Surgery Can Damage His or Her Brain
• Anesthesia Effects on the Fetus and Newborn

Visit SmartTots in Concourse A!

American Academy of Pediatrics National Conference & Exhibition

October 20-23, 2012, New Orleans, LA Related Sessions

• Joint Surgery Conference – Anesthesia Neurotoxicity: Are We Poisoning Children’s Brains?

Visit the SmartTots booth at the Surgical Reception following the Joint Surgery Conference!

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

Caleb Ing, MD Columbia University Anesthetic Exposure Duration and Effects on Cognitive and Language Ability Robert 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 Ansgar 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

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).

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 (p75^NTR) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75^NTR. Read 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?

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.

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.

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.

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.

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.

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