SmartTots Newsletter

Archived Articles

2017 Archive

September/October

 

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

 

 


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

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

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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January/February

Funding Research to Ensure Pediatric Anesthesia Safety

January/February 2017 Newsletter

IARS SmartTots is conducting a search for a Program Officer

Look for us during 2017 at the following events:

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

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

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

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

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

Research News & Updates

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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2016 Archive

November/December

IARS SmartTots is conducting a search for a Program Officer

Look for us during 2017 at the following events:

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

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

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

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

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

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

May 13 – 14, 2017, Genoa, Italy

Research News & Updates

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Special Newsletter Edition: 2016 PANDA Symposium

Special Newsletter Edition: 2016 PANDA Symposium pandastudylogo

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

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

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

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

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

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

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

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

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

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What Next After GAS and PANDA? August 2016

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

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

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

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Mechanisms for Research Support. October 2016

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

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Lessons Learned: Studying the Vulnerable Brain. October 2016

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

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Optimal Timing of Surgical Procedures in Pediatric Patients. October 2016

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

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

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

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

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

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Analysis of MRI Utilization in Pediatric Patients. August 2016

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

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chalkboard_holiday

September/October

IARS thanks the FDA for its renewed support of the

SmartTots Public-Private Partnership!

Look for us during 2017 at the following events:

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

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

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

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Research News & Updates

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

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

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The effect of anaesthesia on the infant brain. September 2016

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

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

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

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

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

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

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

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

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

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

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

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

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

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Carbon monoxide and anesthesia-induced neurotoxicity. September 2016

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

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

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

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

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

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

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

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

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

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

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

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

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

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July/August

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

newsletter2015_2017eurostarconference

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.

Read More

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May/June

 

weHaveYourBabysBack

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

newsletter2015_2017euroStarConference


Research News & Updates

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

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

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

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

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Is anesthesia bad for children’s brains? June 2016

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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March/April

Eat for a Cause

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


2016 PANDA SymposiumpandaStudyLogo

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

panda_groupPhoto


The SmartTots 2015 Annual Report is now available online!

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

Turn your 2015 Tax refund into a 2016 Tax deduction!

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


Call For Papers

Special issue of NEUROTOXICOLOGY AND TERATOLOGY:

Developmental Neurotoxicity Associated with Pediatric General Anesthesia: Preclinical Findings

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


Look for us in 2016 at the following events:

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

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

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

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


Join us for the Second EuroSTAR – SmartTots Scientific Conference:

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


newsletter2015_2017euroStarConferenceResearch News & Updates

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

Read More

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Read More

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Pediatric Anesthesia-Concerns About Neurotoxicity. June 2015

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

Read More

Spring

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

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

The SmartTots 2015 Annual Report is now available online!

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

Look for us in 2016 at the following events:

iars_annual_meeting_2016

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


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

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

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

newsletter2015_2017euroStarConference


Research News & Updates

Ensuring safe anaesthesia for neonates, infants and young children: what really matters, February 2016

Authors say factors affecting long-term brain health and neurocognition in children—other than anesthesia type—require attention; they call for improvements throughout the pediatric anesthesia community: better training and more experience among clinicians, standardized fellowships and clinical guidelines, improvements in dose titration

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Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia, January 2016

Are children with Complex I (CI) deficiency in brain cell respiration (brain energy) more prone to anesthesia-induced brain damage? Researchers find isoflurane has a positive rather than negative effect on the supply of energy to the brain in CI-deficient, post-natal mice.

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Acute and Long-Term Effects of Brief Sevoflurane Anesthesia During the Early Postnatal Period in Rats, January 2016

Study reveals isoflurane causes small changes in synaptic plasticity (which supports learning and memory) and dendritic spine density (associated with memory and mental agility), but no long-term disruption in brain circuits (which allow different regions of the brain to connect and process information in a coordinated way).

Read More


α-Lipoic acid inhibits sevoflurane-induced neuronal apoptosis through PI3K/Akt signalling pathway, January 2016

Study with baby rats shows that a-Lipoic acid, an antioxidant found in all cells, reduces brain cell death in the hippocampus and subsequent cognitive impairment associated with sevoflurane administration.

Read More


Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants, January 2016

Researchers working with pre-term human neonates urge caution with midazolam doses given findings that higher doses are associated with abnormal changes in the brain’s hippocampus and lower cognitive scores.

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Differential Suppression of Spontaneous and Noxious-evoked Somatosensory Cortical Activity by Isoflurane in the Neonatal Rat, January 2016

Study with rats at postnatal ages seven to 30 days measures reactions to noxious stimuli (pain) in the cerebral cortex while under varying levels of isoflurane; finds reactions age dependent with cortical-evoked potentials (a measure of the brain’s response to pain) more resistant to isoflurane in young rats.

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Etomidate exposure in early infant mice does not induce apoptosis or affect behavior, January 2016

Using a mouse model that correlates to early infant behavior in humans, researchers look at the effect of etomidate, ketamine, and propofol on cell death in the cerebral cortex. In conclusion, none of these agents caused cell death, as measured by activated caspase-3 (a protein that plays a role in cell death) concentrations.

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The rise and fall of anaesthesia-related neurotoxicity and the immature developing human brain, January 2016

Authors believe studies in rodents and non-human primates provide the wrong roadmap for clinical care and research in pediatric anesthesia; that emerging findings from robust prospective randomized trials in humans–such as the multi-center GAS Study–are more appropriate and promising for anesthesia and its impact on brain health in children.

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Morphological features of the neonatal brain following exposure to regional anesthesia during labor and delivery, February 2015

Using MRI, researchers study brains of 37 healthy human babies, less than six weeks, exposed to regional anesthesia during labor and delivery. Infants show larger occipital and frontal lobes, and larger brain folds, than 13 babies in the control group. More studies needed to see if larger size correlates with long-term neurobehavioral problems.

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Straight Talk MD’s Dr. Frank Sweeny and Dr. Paul Yost address the question “Does general anesthesia have any long-term effects on learning, memory, or behavior in infants and children?”

Dr. Paul Yost, the Past President of the California Society of Anesthesiologists, joins host Dr. Frank Sweeny on a recent podcast that allays concerns while raising awareness for the need for more research during a discussion of the latest scientific evidence on neurocognitive effects of general anesthesia on infants and children.

Listen Here

Winter

SmartTots needs your help!

If you’ve been following the latest scientific research, you know that the animal studies indicate that certain common anesthetic and sedation drugs appear to harm the developing brain. SmartTots is accelerating efforts to fund research to identify and lessen the risks for children.

Learn how you can help at SmartTots.org/donate


SmartTots Featured at Anesthesiology 2015

Dr. Andrew Davidson facilitated a session entitled Anesthesiology Clinical Trials where he gave an update on selected high-profile clinical trials, all accepted for publication in Anesthesiology. The session also revealed the two year findings of the international, multi-site GAS study.

Researchers active in this area presented Neurotoxicity in the Developing Brain: An Update for the Practitioner

Special thank you to ASA and SPA for their generous support at their 2015 conferences!

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

Look for us in 2016 at the following events:

iars_annual_meeting_2016SmartTots Panel at the IARS Annual Meeting,

Sunday, May 22nd, 2016, 10:30 – 12:00pm

  • SPA-AAP Pediatric Anesthesiology April 2016, Colorado Spring, CO
  • PANDA Symposium, April, 2016 New York, NY
  • Society for Pediatric Anesthesia 30th Annual Meeting, October 2016, Chicago, IL
  • Society for Neuroscience in Anesthesiology and Critical Care, 44th Annual Meeting, October 2016, Chicago, IL
  • American Society of Anesthesiologists – Anesthesiology 2016! October 2016, Chicago, IL

newsletter2015_2017euroStarConferenceSave the Date:

Join us for the Second EuroSTAR – SmartTots Scientific Conference:

Pediatric Anesthesia and Neurotoxicity,

June 8 – 10, 2017, Genoa, Italy


Research News & Updates

The following seven items represent related abstracts presented at the American Society of Anesthesiologists Conference, Anesthesiology 2015:

Latent Class Analysis of Neuropsychological (NP) Deficit After Exposure to Anesthesia in Early Childhood, October 2015

Study of 1444 children associates less severe neuropsychological (NP) deficits with early exposure to anesthesia; severe NP deficits lack the association. Risk factors other than early exposure to anesthesia may lead to severe NP deficits. Read More


Identifying Children at Risk for Anesthetic Neurotoxicity, October 2015

Retrospective cohort study finds one in seven children, given sevoflurane at less than three years of age, at risk for neurotoxicity. Read More


Dexmedetomidine Mitigates Neuroapoptosis Induced by Prenatal Intravenous Anesthetic Exposure in Rats, October 2015

Animal study finds that giving pregnant rats dexmedetomidine, a sedative, prior to propofol and ketamine helps reduce anesthesia-related cell damage in fetal brain tissue. Read More


Development of a Translational, Preclinical Piglet Model of Anesthesia-Induced Neurotoxicity Mechanisms in the Pediatric Population, October 2015

Researchers present a piglet model as ideal way to study impact of anesthesia on neuroinflammation and improve anesthesia safety for children. This model is less costly than other animal models and may prove superior in moving promising findings from the bench to preclinical phases of testing. Read More


Neuroinflammation and Ischemic Neurodegeneration in the Central Nervous System of Newborn Piglets After Isoflurane Anesthesia, October 2015

Study of brains in baby pigs given isoflurane and lipopolysaccharide (LPS) reveals deadly effect these agents have on developing cells in the cortex and hippocampus, along with their potential to block the flow of blood and oxygen to the brain. Read More


Estimation and Analysis of Unnecessarily Early Procedures in Infants Younger than Six Month of Age in the United States, October 2015

Analysis finds more than 8,500 unnecessary surgical procedures per year in the U.S. on infants less than six months. Higher rates occur in certain states and to families with private insurance or no insurance more so than to those in government-sponsored health plans. Read More


Neonatal MRI: Can We Reduce Anesthesia Exposure? A National Survey, October 2015

Survey of all U.S. NICUs (with 60% response rate) concludes that, for MRI of the brain in neonates, the first-line method for keeping the baby motionless should be the feed and swallow technique (FS) versus use of sedation and general anesthesia (GA). Read More


A Less Risky Anesthesia for Babies, December 2015

The author discusses ongoing research efforts aimed at clarifying the benefits and risks, including impairments in cognitive function, of spinal anesthesia over general anesthesia for infants and toddlers undergoing surgery. Spinal anesthesia is proving successful for certain types of surgeries, but doctors await results of new studies on long-term effects. Read More


Information, Communication Lacking for Neurotoxicity in Pediatric Anesthesia, December 2015

Results of a survey from Children’s Hospital of Philadelphia to leaders in the anesthesia community reveals a widespread lack of consistency in the approach to managing anesthesia-related toxicity in children, calls for more education to clinicians, professionals, and parents on the state of the science. Read More


Anesthesia-Induced Neuronal Apoptosis in the Developing Retina: A Window of Opportunity, November 2015

Using MRI technology, researchers observe cell death in the retinas of rats exposed to isoflurane. Findings offer a promising, non-invasive approach for measuring the neurotoxicity of isoflurane in the brains of infants and children. Read More


Steven Roth, MD, Department of Anesthesiology, University of Illinois, responds in an Editorial.

Dr. Roth commends Cheng and colleagues for advancing a non-invasive method for seeing the toxic effect of isoflurane on cells in the retina of rats; a method that, one day, may help scientists study the effect of anesthesia on human brain cells in real time. Read More


Negotiating the dilemma of anaesthesia and sedation in NICUs, October 2015

The author highlights a lack of clinical guidelines for prolonged use of anesthesia and sedation in neonates. He encourages further interpretation of findings from the Europain Study, which he believes will translate into practice improvements and better patient safety. Read More


Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial, October 2015

Using the Bayley Scales (a standard series of measurements used to assess motor, language, and cognitive development of infants and toddlers), researchers find the secondary outcome, a composite cognitive score, in the GAS trial. They report no significant difference in mean scores for children assessed at age two who received less than one hour of sevoflurane versus awake-regional anesthesia for a hernia repair. Read More


Long-Term Behavioral Effects in a Rat Model of Prolonged Postnatal Morphine Exposure, October 2015

Newborn rats given morphine show less tolerance to heat stimulation in stress tests when compared to rats given saline only. This hypersensitivity to heat for newborns on morphine is associated with an increased sensitivity to pain in adulthood. Read More


Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study, October 2015

A study of 6680 neonates in 243 NICUs within 18 European countries shows a wide variation in sedation practices and a need for more research.  Scientists assessed pain, drug withdrawal syndromes, and the association between tracheal ventilation, exposure to opioids, sedative-hypnotics, and general anesthesia. Read More


General Anesthesia in Peds May Affect Brain Development and IQ Scores, September 2015

The author addresses questions that remain about the effects of general and regional anesthesia on the child’s brain. She highlights research and commentary from Dr. Andreas Loepke at Cincinnati Children’s; Dr. Andrew Davidson at Melbourne Children’s Trials Center; and Dr. Geoff Fawley at Royal Children’s in Melbourne. Read More


Neonatal anesthesia: how we manage our most vulnerable patients, September 2015

This review defines the unique challenges for high-risk neonates undergoing surgical procedures and anesthesia exposure.  The authors call for greater sensitivity to the needs of these babies and meticulous medical management in an effort to improve overall outcomes. Read More


Pediatric dental sedation: challenges and opportunities, August 2015

Some sedation in children’s dental procedures has led to death and impairment, including permanent brain damage.  The authors explore sedation agents and methods currently in use and on the horizon that promise greater safety with less toxicity and trauma to the patient. Read More


Efficacy of rutin in inhibiting neuronal apoptosis and cognitive disturbances in sevoflurane or propofol exposed neonatal mice, August 2015

Research with baby rats finds that combining rutin, a natural substance in plants and foods, with sevoflurane and propofol administration reduces the toxic effects of these drugs on brain cells, including those associated with memory and cognition. Read More


Anesthetic use in newborn infants: the urgent need for rigorous evaluation, July 2015

Authors highlight the need for more research and clinical guidance on the safety, toxicity, and effectiveness of drugs used as anesthesia and analgesia on neonates and infants.  There have been few drug label updates for newborns and none for premature infants; “off-label” drugs frequently used in this population require more testing. Read More


Age-dependency of sevoflurane-induced electroencephalogram dynamics in children, July 2015

How EEG patterns, measuring electrical activity in the brain, go up and down in children exposed to general anesthesia is not well understood.  Researchers observe alpha wave coherence–a correlation of EEG signals at different scalp locations–to be high in adults, but absent in one-year olds under sevoflurane, revealing its variable effect by age on developing brain circuits. Read More


Long-term action of propofol on cognitive function and hippocampal neuroapoptosis in neonatal rats, July 2015 

Study shows low doses of propofol to be safe during early brain growth in baby rats, but repeated mid to high doses can lead to cell death, inflammation, and impaired cognitive function. Read More


Neuroprotective properties of vitamin C on equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in high fat diet fed neonatal mice, July 2015

Researchers, working with normal weight and obese baby mice, find that administering vitamin C along with desflurane, isoflurane or sevoflurane reduces the toxic effects of these agents by protecting against brain cell death and reducing impairments in memory and learning. Read More


Propofol: A Review of its Role in Pediatric Anesthesia and Sedation, July 2015

Use of propofol in children needing sedation is common, but this drug is currently off-label for children, meaning it lacks guidelines for use with pediatric patients.  In this review, the authors discuss the pros and cons of propofol use in children, vis-à-vis side effects, complications, and neurotoxicity. Read More


Surgical Anesthesia in Young Children Linked to Effects on IQ, Brain Structure, June 2015

A retrospective study from Cincinnati Children’s finds children exposed to general anesthesia score five to six points lower in listening comprehension and performance IQ, which may translate to a lifetime in lost wages.  For the 6 million children in the U.S. who undergo surgery every year, this is a lifetime potential earnings loss of $540 billion. Read More


Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants, June 2015

Observational study examines brain wave oscillations using multi-electrode EEG and “multitaper spectral methods” with infants on sevoflurane; finds decrease in theta and alpha brain waves as infants four to six months emerge from surgery and sevoflurane level goes down.  More sensitive brain monitoring methods, like this, may offer new strategies for lowering anesthesia risk in children. Read More


The Anesthesia Dilemma: Researchers are trying to determine if chemicals used to knock out young children during surgery can have long-term repercussions on memory and development, June 2015

Recent animal studies find general anesthesia harmful to brain development, cognition, and memory, but measuring the degree of deficit in humans is difficult; variables other than anesthesia exposure may be at play.  The author describes new studies and video games with children that may offer insight into the link between anesthesia and cognitive deficits. Read More


SmartTots wishes all of our subscribers a happy and healthy 2016!

2015 Archive

Fall

If you’ve been following the latest scientific research, you know that the animal studies indicate that certain common anesthetic and sedation drugs appear to harm the developing brain. SmartTots is accelerating efforts to fund research to identify and lessen the risks for children.

Learn how you can help at SmartTots.org/donate


Consensus Statement on the use of Anesthetic and Sedative Drugs in Infants and Toddlers

Join us for the Second EuroSTAR – SmartTots Scientific Conference:  Pediatric Anesthesia and Neurotoxicity, June 8 – 10, 2017, Genoa, Italy 


Research News & Updates 

Recent Study Shows No Difference between General Anesthesia and Regional Anesthesia in Short Duration Surgery, October 2015

GAS study researchers release report describing the secondary outcome of cognitive performance at 2 years of age based on 532 subjects. Read More


SmartTots responds to the release of the GAS Study results with a Supplement to the Consensus Statement.  Read More


microRNA Expression Profiling of Propofol-Treated Developing Rat Hippocampal Astrocytes, June 2015

Our results shed light on the anesthetic mechanism of propofol and have implications for its use in the clinical setting. Read More


Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy, June 2015

There is a particular need to examine the impact of the choice of spinal over general anaesthesia on respiratory and neurological outcomes in high-risk infant subgroups with severe respiratory disease and previous brain injury. Read More


Cognition and Brain Structure Following Early Childhood Surgery With Anesthesia, June 2015

The present findings suggest that general anesthesia for a surgical procedure in early childhood may be associated with long-term diminution of language abilities and cognition, as well as regional volumetric alterations in brain structure. Read More

Joshua J Davis, Medical Student at Sidney Kimmel Medical College, Thomas Jefferson University responds in a letter to the editor. Read More

Thomas Engelhardt, Pediatric Anesthesiologist, Department of Anaesthesia, Royal Aberdeen Children’s Hospital responds in a letter to the editor. Read More


Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells, June 2015

Quantitative analysis shows that the number of differentiated neurons was substantially reduced in 10μM ketamine-exposed cultures in differentiation medium, compared with the controls. Read More


Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum, June 2015

Exposure of immature rats to general anesthesia during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum. Read More


Long-term NMDA receptor inhibition affects NMDA receptor expression and alters glutamatergic activity in developing rat hippocampal neurons, June 2015

Long-term blockade of the NMDA receptor in developing rat hippocampal neurons significantly increased NR1 subunit expression, and that this was associated with an alteration in neuronal activity. Read More


Safe Anesthesia For Every Tot – The SAFETOTS initiative, June 2015

The improvement of teaching, training, education and supervision of the safe conduct of pediatric anesthesia are the main goals of the safetots.org initiative. Read More


Is this your (paediatric patient’s) brain on (anaesthetic) drugs?: The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans, May 2015

Given the immense importance for individual wellbeing as well as societal health, intensified research efforts are needed to determine whether or not surgical procedures with general anaesthesia have any long-term effects on the developing human brain. Read More


Risk of autistic disorder after exposure to general anaesthesia and surgery: A nationwide, retrospective matched cohort study, May 2015

Exposure to general anaesthesia and surgery before the age of 2 years age at first exposure and number of exposures were not associated with the development of autistic disorder. Read More


Carbon monoxide modulates Cytochrome Oxidase Activity and Oxidative Stress in the Developing Murine Brain During Isoflurane Exposure, May 2015

Carbon monoxide-mediated effects could have implications for the development of low-flow anesthesia in infants and children in order to prevent anesthesia-induced oxidative stress. Read More


Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, A Randomized Controlled Trial, May 2015

RA in infants undergoing inguinal herniorrhaphy reduces apnea in the early postoperative period. Read More


Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair: Data from the General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, May 2015

Awake regional anesthesia is a viable alternative to general anesthesia for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes. Read More


Elevation of Sestrin-2 expression attenuates Sevoflurane induced neurotoxicity, May 2015

These results suggest that the suppressive effects of Sestrin-2 on neuroapoptosis against the Sevoflurane anesthesia in neuronal cells might be associated with modulation of mitochondrial pathway. Read More


Impact of propofol anaesthesia on cytokine expression profiles in the developing rat brain: A randomised placebo-controlled experimental in-vivo study, May 2015

This study suggests that propofol anaesthesia does not have a major impact on pro-inflammatory cytokine expression profiles in the developing central nervous system during the brain growth spurt. Read More


Regional anaesthesia in neonates, infants and children: An educational review European Journal of Anaesthesiology, May 2015

Performing regional blocks in anaesthetised children is a safe and generally accepted practice. Read More


Anesthesia and the developing brain: a way forward for clinical research, May 2015

It may be impossible to conduct a single study to exclude the possibility that anesthetics can produce long-term neurobehavioural changes in humans; however, observational studies will improve our understanding of which children are at greatest risk, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome. Read More


Dexmedetomidine Attenuates Neurotoxicity Induced by Prenatal Propofol Exposure, April 2015

Dexmedetomidine attenuates neuronal injury induced by maternal propofol anesthesia in the fetal brains, providing neurocognitive protection in the offspring rats. Read More


Perioperative effects of caudal and transversus abdominis plane (TAP) blocks for children undergoing urologic robot-assisted laparoscopic surgery, April 2015

Administration of caudal blocks should be considered for children of suitable age undergoing RAL surgery involving either the upper or lower urinary tract. Read More


Only extra-high dose of ketamine affects l-glutamate-induced intracellular Ca2+ elevation and neurotoxicity, April 2015

Long-term exposure to TPS or ketamine at clinical doses during developmental periods may not result in a dose-related potentiation of exogenous glutamate-induced neurotoxicity, once the intravenous anesthetics are discontinued. Read More


Developmental stage-dependent impact of midazolam on calbindin, calretinin and parvalbumin expression in the immature rat medial prefrontal cortex during the brain growth spurt, April 2015

These data provide us with one potential mechanism that could account for the lasting neurobehavioral and cognitive deficits observed in the context of anesthesia exposure in the early postnatal period. Read More


Neurotoxicity of Generic Anesthesia Agents in Infants and Children: An Orphan Research Question in Search of a Sponsor, April 2015

More studies and trials are needed to address questions about the optimal dose, duration, and frequency of use of anesthetic agents and vulnerable periods of exposure in young children. Read More


Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats, April 2015

A subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. Read More


Neurodevelopmental implications of the general anesthesia in neonate and infants, April 2015

In this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies. Read More


Repeated Exposure to Ketamine-Xylazine during Early Development Impairs Motor Learning-dependent Dendritic Spine Plasticity in Adulthood, April 2015

Our study demonstrates that repeated exposures to ketamine-xylazine during early development impair motor learning and learning-dependent dendritic spine plasticity later in life. Read More


Safety and feasibility of xenon as an adjuvant to sevoflurane anaesthesia in children undergoing interventional or diagnostic cardiac catheterization: study protocol for a randomised controlled trial, March 2015

Xenon provides remarkable haemodynamic stability and potentially has cardio- and neuroprotective properties. Unfortunately, evidence is scarce on the use of xenon in the paediatric population. Read More


Anesthetic-Related Neurotoxicity in Children – ASA Works in Close Cooperation With FDA and Others to Advance Research, March 2015

Based on their latest approach to investigating and funding studies of anesthetic neurotoxicity, SmartTots and the FDA have been increasingly determined to position the research to hone in on the question of whether the increased risk of cognitive deficits seen in some studies is truly a result of the anesthetic medications or due to another reason entirely. Read More


Interventional Procedures for Chronic Pain in Children and Adolescents: A Review of the Current Evidence, March 2015

The potential for severe complications resulting from interventional procedures in the treatment of chronic pain for children and adolescents leaves open a debate on the safety of these procedures, which must be confirmed by more extensive and accurate prospective studies. Read More


Special aspects of pediatric anesthesia in ophthalmic surgery, February 2015

In animal experiments it could be proven that neuronal apoptosis could be induced by most of the commonly used anesthetics. It has not yet been clarified whether this has an effect on the neurocognitive development of children. There is, however, widespread agreement that a necessary anesthesia carried out in a correct and controlled manner has no negative consequences for children. Read More


Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study, February 2015

Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Read More


Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice, January 2015

Curcumin pre-administration can prevent the sevoflurane exposure-induced cognitive impairment later in life, which may be partly attributed to its ability to attenuate the neural apoptosis, inflammation, and oxidative nitrosative stress in mouse brain. Read More


Single sevoflurane exposure increases methyl-CpG island binding protein 2 phosphorylation in the hippocampus of developing mice, January 2015

Sevoflurane causes neurotoxicity in the developing brain. This neurotoxicity can be prevented by the N-methyl-D-aspartate glutamate receptor inhibitor memantine. Read More


Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure, January 2015

These findings suggest a “threshold effect for general anesthetic-induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss. Read More

March

Latest Updates from the IARS Annual Meeting, March 21-24, Honolulu, HI

Video Presentation Neurotoxicity of Anesthetics in the Developing Brain – A Translational Update Recorded live on March 23 at the IARS Annual Meeting in Honolulu, HI. Panelists: Ansgar Brambrink, MD, PhD; Andreas W. Loepke, MD, PhD; Vesna Jevtovic-Todorovic, MD, PhD, MBA; Andrew Davidson, MBBS, MD, FANZCA


SmartTots-Related Abstract Judged Best of Meeting Academic Performance After Anesthesia and Surgery During Childhood: A Large-Scale Nation-Wide Study Pia Glatz, MD, R. H. Sandin, N. L. Pedersen, A. E. Bonamy, L. I. Eriksson, F. N. Granath


Research News & Updates

Anesthetic neurotoxicity–clinical implications of animal models. The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age. Read more


Neurodevelopment of children exposed to anesthesia: Design of the Mayo Anesthesia Safety in Kids (MASK) study The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks. Read more


Is There Evidence for Long-Term Neurocognitive Effects of Sedatives Given the public health implications of anesthetic and sedative drugs on the developing brain, this chapter will discuss relevance of these issues in the context of the management of sedation in pediatric patients undergoing diagnostic and painful procedures.  Read more


A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia fMRI appears to be a useful tool in evaluating the long-term effects of early exposure to general anesthesia. Read more


Dexamethasone but not the equivalent doses of hydrocortisone induces neurotoxicity in neonatal rat brain. Hydrocortisone is probably safer to use than dexamethasone in the immediate postnatal period in neonatal rats. Cautious extrapolation of these findings to human premature infants is required. Read more


Altered Metabolomic Profiles May Be Associated with Sevoflurane-Induced Neurotoxicity in Neonatal Rats. Our data indicate that sevoflurane anesthesia causes significant oxidative stress, neuroapoptosis, and cellular ultrastructure damage, which is associated with altered brain metabotype in the neonatal rat. Read more


Hyperexcitability of Rat Thalamocortical Networks after Exposure to General Anesthesia during Brain Development Drugs that regulate thalamic excitability may improve the safety of GAs used during early brain development.  Read more


Repeated Exposure to Ketamine-Xylazine during Early Development Impairs Motor Learning-dependent Dendritic Spine Plasticity in Adulthood Repeated exposures to ketamine-xylazine during early development impair motor learning and learning-dependent dendritic spine plasticity later in life. Read more


Neuroprotective effects of pterostilbene against isoflurane-induced apoptosis through regulating the JNK and PI3K/Akt pathway in neonatal rats Observations suggest that pterostilbene was able to effectively reduce isoflurane-induced neurodegeneration. Read more


Effect of apoptosis in neural stem cells treated with sevoflurane Sevoflurane can inhibit the central nervous system by activating γ-Aminobutyric acid (GABA) is a known inhibitory neurotransmitter in central nervous system.  The result is apoptosis of neural stem cells, thus leading to the NSCs degeneration. Read more


Molecular pathways of mitochondrial dysfunctions: Possible cause of cell death in anesthesia-induced developmental neurotoxicity. The molecular processes of mitochondrial dysfunction should be understood to develop novel therapeutic strategies that can prevent anesthesia-induced neurotoxicity and provide neuroprotection against developmental central nervous system. Read more


Propofol inhibits proliferation and induces neuroapoptosis of hippocampal neurons in vitro via downregulation of NF-κB p65 and Bcl-2 and upregulation of caspase-3 These results indicated that downregulation of NF-κB p65 and Bcl-2 likely led to the caspase-3 activation, triggered apoptosis and inhibited the neuronal growth and proliferation that we have observed in our in vitro systems. Read more


Pre-treatment with a Xingnaojing preparation ameliorates sevoflurane-induced neuroapoptosis in the infant rat striatum. These data suggest that the standardized Chinese herbal medicine XNJ has an antiapoptotic effect against sevofluraneinduced cell loss in the striatum. It thus holds promise as a safe and effective neuroprotective agent. Read more


Safety and feasibility of xenon as an adjuvant to sevoflurane anaesthesia in children undergoing interventional or diagnostic cardiac catheterization: study protocol for a randomised controlled trial. Read More

2014 Archive

December

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

November

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

September

Research News & Updates

Cognitive Outcome after Spinal Anesthesia and Surgery During Infancy

Our study found no link between duration of surgery with infant spinal anesthesia (SA) and scores on academic achievement testing in elementary school. We also found no relationship between infant SA and surgery with very poor academic achievement (VPAA) on elementary school testing, although the confidence intervals (CIs) were wide. Read more


Cognitive Outcomes After Infant Spinal Anesthesia: The Other Side of the Coin

In their study, Williams etal. have provided us with aglimpse at thepreviouslyunseen flip sideof the anesthesia-surgerycoin assessing whether asurgicalprocedure maycontribute to adversecognitive outcome laterinchildhood. Read more


Neonatal Anesthesia Neurotoxicity: A Review for Cleft and Craniofacial Surgeons

The timing and number of cleft and craniofacial surgeries in our treatment protocols may need to be reevaluated to account for these potential risks. Read more


Erythropoietin protects newborn rat against sevoflurane-induced neurotoxicity

Six hours of sevoflurane anesthesia in newborn rats induces significant long-term cognitive impairment. A single administration of rh-EPO immediately after postnatal exposure to sevoflurane reduces both early activation of apoptotic phenomenon and late onset of neurologic disorders.  Read more


Isoflurane impairs the capacity of astrocytes to support neuronal development in a mouse dissociated coculture model.

Isoflurane interferes with the ability of cultured astrocytes to support neuronal growth. This finding represents a potentially novel mechanism through which general anesthetics may interfere with brain development. Read more


Role of miR-34c in ketamine-induced neurotoxicity in neonatal mice hippocampus

Cognitive examination with the Morris water maze test showed that ketamine-induced memory impairment was significantly improved by miR-34c downregulation.Read more


Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix. Read more

August

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

July

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

May 2014

Mark your calendar!

SmartTots Workshop

Friday, June 20, 2014: Crystal City Marriott at Reagan National Airport, Washington, DC

Open to all interested professionals. No registration fee.

Workshop Objectives:

  1. Develop a shared understanding of the recent and ongoing studies regarding pediatric anesthesia neurotoxicity, including rationale, study design, and results to date.
  2. Determine what additional studies are needed, including study design and cost.
  3. Identify strategies for a proposal to government sources to raise the funds required to conduct the needed studies.

Please contact Rebekah Davies, IARS Program Manager for more information or to register for the workshop. rdavies@iars.org   415-296-6905


Research News & Updates

Comparative Analysis of Outcome Measures Used in Examining Neurodevelopmental Effects of Early Childhood Anesthesia Exposure

When assessing cognition in children with early exposure to anesthesia, the results may depend on the outcome measure used. Neuropsychological and International Classification of Diseases, 9th Revision, Clinical Modification-coded clinical outcomes showed an increased risk of deficit in exposed children compared with that in unexposed children, whereas academic achievement scores did not. This may explain some of the variation in the literature and underscores the importance of the outcome measures when interpreting studies of cognitive function.  Read more


The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. 

After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12 months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes.  Read more


Anesthetic neurotoxicity

This article provides an overview of the currently available data from both animal experiments and human clinical studies regarding the effects of sedatives and anesthetics on the developing brain.  Read more


Anesthesia and the Developing Brain: Relevance to the Pediatric Cardiac Surgery

Children potentially at greater risk for anesthetic neurotoxicity, based on a prolonged anesthetic exposure early in development, are those receiving anesthesia for surgical repair of congenital heart disease. These children not only receive prolonged anesthetic exposure during surgical repair but also repeated anesthetic exposures during a critical period of brain development. Their propensity to abnormal brain development, as a result of congenital heart disease, may modify their risk of anesthetic neurotoxicity. This review article provides insight into basic science and clinical investigations as it relates to this unique group of children.  Read more


Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.  Read more


Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. We summarize laboratory data published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function, and we discuss findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.  Read more


Basic aspects of the potential toxicity of anesthetic drugs

During the last decade, numerous in vitro and in vivo experimental studies in newborn animal models have established the neurotoxic effects of most anesthetic and sedative drugs used in pediatrics.  These data are insufficient to change our practices, however progress in experimental research will help us identify the safest therapeutic strategies and neuroprotective treatments.   Read more


Subclinical Carbon Monoxide Limits Apoptosis in the Developing Brain After Isoflurane Exposure

It is possible that low-flow anesthesia designed to target rebreathing of specific concentrations of CO may be a desired strategy to develop in the future in an effort to prevent anesthesia-induced neurotoxicity in infants and children.  Read more


Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains

The underlying mechanism by which dexmedetomidine reduces neuronal injury during a prolonged anesthesia remains unclear. In this study, we compare the neurotoxic effects of dexmedetomidine and ketamine, a general anesthetic with a different mechanism of action, in fetal cynomolgus monkeys.  In utero treatment with ketamine resulted in marked apoptosis and degeneration primarily in layers I and II of the frontal cortex. In contrast, fetal brains from animals treated with dexmedetomidine showed none to minimal neuroapoptotic or neurodegenerative lesions at both low- and high-dose treatments.  Read more


Dexmedetomidine Reduces Isoflurane-Induced Neuroapoptosis Partly by Preserving P13K/Akt Pathway in the Hippocampus of Neonatal Rats

Prolonged exposure to volatile anesthetics, such as isoflurane and sevoflurane, causes neurodegeneration in the developing animal brains. Recent studies showed that dexmedetomidine, a selective α2-adrenergic agonist, reduced isoflurane-induced cognitive impairment and neuroapoptosis. The mechanisms for the effect are not completely clear.  Our results suggest that dexmedetomidine pretreatment provides neuroprotection against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats by preserving PI3K/Akt pathway activity.  Read more


Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females

There is mounting evidence that children exposed to anesthetic agents sustain lasting effects on learning and memory. Rodent models have shown that isoflurane exposure in newborns induces acute neuroapoptosis and long-term cognitive impairment.  In our study on male and female Sprague Dawley rats, we found that isoflurane exposure significantly increased neuronal death in each brain region with no difference between sexes. However, only males were impaired in the recognition of objects in different locations and contexts. Males also exhibited deficient social memory while females were intact.  Read more


Exposure to general anesthesia in early life and the risk of attention deficit/hyperactivity disorder development: a nationwide, retrospective matched-cohort study

Exposure to general anesthesia before 3 years of age was not associated with ADHD.  Read more


Neuroprotective gases–fantasy or reality for clinical use?

In this review, we summarize the literature concerning the neuroprotective effect of each gas and its underlying mechanisms, extract common targets reported for the neuroprotective effects of different gases, highlight the conflicting observations from clinical trials and further discuss the possible hindrances impeding clinical applications in order to propose future research perspectives and therapeutic exploitations.  Read more


Neonatal Morphine in Extremely and Very Preterm Neonates: Its Effect on the Developing Brain, a Review

Preterm infants requiring intensive care experience procedures requiring management of stress and pain. This overview of research on the use of morphine and its neurodevelopmental effects on neonates finds no definite conclusions concerning the effects of neonatal morphine on long term neurodevelopmental outcomes. More prospectively designed trials should be conducted using reliable and validated pain assessment scores to evaluate effects of morphine on long term neurodevelopmental outcomes in preterm infants.  Read more

March

March 2014

Mark your calendar!

SmartTots Workshop

Friday, June 20, 2014: Sheraton Crystal City Hotel, Washington, DC

Open to all interested professionals. No registration fee.

Workshop Agenda:

  • Updates on the ongoing studies, including results to date
  • Additional studies needed to answer the questions about the potential neurotoxicity of anesthetics in the developing human brain
  • Dealing with the uncertainties about anesthetics and children in the practice environment
  • Does the Consensus Statement on the Use of Anesthetics and Sedatives in Children need revision?
  • Raising the funds required to conduct the needed studies

Please contact Rebekah Davies, IARS Program Manager for more information or to register for the workshop. rdavies@iars.org   415-296-6915


Research News & Updates

Functional implications of an early exposure to general anesthesia: are we changing the behavior of our children?

A review of presently available evidence regarding anesthesia-induced neurocognitive and social behavioral impairments and possible strategies for preventing them, and of limited and somewhat controversial evidence that examines the effects of nociception and surgical stimulation on anesthesia–induced developmental neurotoxicity. Read more


 Anesthesia considerations in pediatric glaucoma management

As the potential long-term adverse neurodevelopmental effects of general anesthesia become better understood, pediatric glaucoma specialists should be cognizant of the relative lifelong risks and benefits of repeat examinations under anesthesia in young patients. Read more


 Adverse effect of inhalational anesthetics on the developing brain

Experimental studies using animal models have indicated some adverse effect of anesthetics, especially neurotoxicity, in the developing brain.  More evidence is needed before a recommendation can be made to change the way those anesthetics are used in the pediatric population. Two clinical trials underway may provide insight to the potential human neurotoxic effect of anesthetics. Read more


 Dual effects of ketamine: neurotoxicity versus neuroprotection in anesthesia for the developing brain

Ketamine is widely used in pediatric anesthesia.  Animal studies have shown that ketamine may have neurotoxic effects on the developing brain.  Other studies have shown ketamine protects the central nervous system by inhibiting inflammation in the developing brain.  Balancing the neurotoxic and neuroprotective effects of ketamine on the developing brain may be possible, but further study is required. Read more


 Isoflurane-induced Apoptosis of Neurons and Oligodendrocytes in the Fetal Rhesus Macaque Brain

Isoflurane anesthesia for 5 hours causes death of neurons and oligodendrocytes in the G120 fetal NHP brain. In the fetal brain, as the authors previously found in the neonatal NHP brain, oligodendrocytes become vulnerable when they are just achieving myelination competence. The neurotoxic potential of isoflurane increases between the third trimester (G120) and the neonatal period in the NHP brain. Read more


 Anesthesia for the young child undergoing ambulatory procedures: current concerns regarding harm to the developing brain.

Sedation and anesthesia are often necessary for children at any age, and are frequently provided in ambulatory settings. Concerns have mounted, based on both laboratory studies including various mammalian species and retrospective human clinical studies, that the very drugs that induce sedation and anesthesia may trigger an injury in the developing brain, resulting in long-lasting neurobehavioral consequences. Read more


 The potential dual effects of sevoflurane on AKT/GSK3beta signaling pathway.

Anesthetic sevoflurane might induce a dual effect (increase versus decrease) on the activation of the AKT/GSK3beta signaling pathway. These studies have established a system to perform further studies to determine the effects of sevoflurane on brain function. Read more


 Physiological disturbance may contribute to neurodegeneration induced by isoflurane or sevoflurane in 14 day old rats.

Volatile anesthetics are widely used in pediatric anesthesia but their potential neurotoxicity raise significant concerns regarding sequelae after anesthesia.  These findings could suggest physiological disturbance induced by isoflurane or sevoflurane anesthesia may also contribute to their neurotoxicity. Read more


 Early life exposure to sevoflurane impairs adulthood spatial memory in the rat.

Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit. Read more


Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study.

Young age at anesthetic exposure is believed to be critical, but human studies are scarce. This study found children operated for pyloric stenosis (PS) before 3 months of age have educational performance tests similar to the background population at age 15-16 years after adjusting for known confounders. The higher nonattainment rate could suggest that a subgroup of PS children is developmentally disadvantaged. Read more


 Modeling anesthetic developmental neurotoxicity using human stem cells.

Development of an in vitro neurogenesis system using human stem cells has opened up avenues of research for advancing our understanding of human brain development and the issues relevant to anesthetic-induced developmental toxicity in human neuronal lineages. Read more

2013 Archive

October

SmartTots Featured at Anesthesiology 2013

Special thank you to ASA, SNACC, and SPA! SmartTots would like to extend a special thank-you to the American Society of Anesthesiologists, the Society for Neuroscience in Anesthesiology and Critical Care, and the Society for Pediatric Anesthesia for providing SmartTots with complimentary booth space at the their annual meetings in San Francisco this month. We continue to receive much support from affiliated organizations and its members.


Research News & Updates

A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses. Concern has been expressed that infants and children exposed to uneventful surgery and anesthesia may incur neurological injury that becomes manifest in poor scholastic performance or future learning difficulties. A recent meta-analysis of seven clinical studies examined the relationship between learning or behavior difficulties and pediatric exposure to anesthesia/surgery and reported an odds ratio of 1.4; however, the level of association and causal factors remain unclear. The purpose of our study is to provide context to the pediatric anesthesia neurotoxicity question by reviewing the evidence linking four childhood illnesses with neurocognitive development. In the present review, we have sought to quantify the magnitude of the impact of chronic illness on neurocognitive development through a systematic review of publications that report the developmental trajectory of patients with four childhood diseases: cystic fibrosis (CF), hemophilia A, end-stage renal disease (ESRD) and end-stage liver disease (ESLD). Read more


Neurotoxicity of general anesthetics in childhood: does anesthesia leave its mark on premature babies, newborns and infants? Many animal experiments have shown that anesthetics can have a neurotoxic effect on immature brains because they induce apoptosis and influence neurogenesis and synaptogenesis. In animal experiments this has substantial implications for the neurocognitive functions of animals in later life. Whether these results of animal experiments can be transferred to humans is currently the subject of intensive research. In several retrospective studies no clear association between anesthesia in premature babies, newborns or infants and the occurrence of learning disorders or behavioral problems could be found.  Read more

August

SmartTots Funds $400,000 for Pediatric Anesthesia Research

SmartTots is dedicated to funding research that will help determine if any particular anesthetic or sedative drugs pose hazards to young children, design the safest anesthetic and sedative regimes, and potentially foster the development of new practice guidelines and anesthetic drugs. In support of this goal, two research grants for $200,000 each paid over two years were recently awarded to: Dr. Lena Sun, Columbia University Medical Center in support of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Study Dr. Jeffrey Sall, University of California San Francisco in support ofRecognition Memory Following Early Childhood Anesthesia Click here to view the full media release regarding the 2013/2014 grant awardees.


Research News & Updates

FDA Consumer Update Released: Anesthesia: Is it Safe for Young Brains? When infants or young children need surgery, does anesthesia affect their developing brains? With more than 1 million children under age 4 requiring anesthesia for surgery in the United States each year, the Food and Drug Administration (FDA) and other health organizations are working together to answer this question. Read more


Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss Volatile anesthetics are widely used in the clinic, and sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia. Recent findings question the potential risks of volatile anesthetics on brain development. Evidence suggests that sevoflurane may cause neuronal deficiency. This study investigates the long-term effect of sevoflurane in the developing brain. Read more


Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain Exposure of the fetal or neonatal non-human primate (NHP) brain to isoflurane or ketamine for 5 h causes widespread apoptotic degeneration of neurones, and exposure to isoflurane also causes apoptotic degeneration of oligodendrocytes (OLs). The present study explored the apoptogenic potential of propofol in the fetal and neonatal NHP brain. Read more


Ketamine as anesthetics can damage children’s learning and memory ability Recent studies have found that anesthesia drugs have neurotoxicity on the developing neurons, causing learning and memory disorders and behavioral abnormalities. Ketamine is commonly used in pediatric anesthesia. A clinical retrospective study found that children below 3 years old who receive a long time surgery, or because of surgery require ketamine repeatedly will exhibit the performance of school-age learning and memory disorders and behavioral abnormalities. Read more


Characterization and Quantification of Isoflurane-Induced Developmental Apoptotic Cell Death in Mouse Cerebral Cortex Accumulating evidence indicates that isoflurane and other, similarly acting anesthetics exert neurotoxic effects in neonatal animals. However, neither the identity of dying cortical cells nor the extent of cortical cell loss has been sufficiently characterized. We conducted the present study to immunohistochemically identify the dying cells and to quantify the fraction of cells undergoing apoptotic death in neonatal mouse cortex, a substantially affected brain region.Read more

February

Now Accepting Applications: SmartTots 2013 Research Grants

SmartTots is now accepting applications aimed at investigating whether anesthetics/sedatives are neurotoxic and/or impede the normal development of the human brain. Projects should focus on whether neonatal anesthetic exposure in humans impairs brain development resulting in persistent detrimental effects on cognition or behavior. Studies aimed at identifying either specific anesthetic techniques that do not produce neurotoxic effects or interventions to ameliorate damage will also be considered. Deadline to apply is April 12, 2013. Get started on your application.


IARS 2013 Annual Meeting

The IARS 2013 Annual Meeting in San Diego (May 4-7) will include three panels on the safety and potential impact of pediatric anesthesia.

  • SmartTots Panel: Update on New Scientific Advances in Anesthetic Neurotoxicity in the Developing Brain
  • ISAP Panel: The Best of the New in Clinical Pharmacology
  • APSF Panel: General Anesthesia for Infants Having Surgery and Elective Procedures: Is it Safe?

Don’t miss the 2013 Party with a Purpose fundraiser, which will raise funds for SmartTots research. Purchase your ticket by April 15th to be entered to win an Apple iPad Mini.


Recent Literature

Anesthetics Interfere with Axon Guidance in Developing Mouse Neocortical Neurons In Vitro via a γ-Aminobutyric Acid Type A Receptor Mechanism The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity. Read more


Dual Effects of Isoflurane on Proliferation, Differentiation, and Survival in Human Neuroprogenitor Cells Previous studies have demonstrated that isoflurane can provide both neuroprotection and neurotoxicity in various tissue culture models and in rodent developing brains. The cellular and molecular mechanisms mediating these dual effects are not clear, but the exposure level and duration of isoflurane appear to be determinant factors. Read more


Prognostic Study of Sevoflurane-Based General Anesthesia on Cognitive Function in Children It is unclear whether volatile general anesthetics have sustained adverse effects on the immature brains of children. The authors performed a self-controlled study to evaluate the effects of strabismus surgery under sevoflurane-based general anesthesia on the cognitive function of pediatric patients. Read more

January

Request for Applications Update

SmartTots will begin accepting applications for its second round of research grants in early February. Two $200,000 grants will be available. View the preliminary RFA.


Recent Literature

Sevoflurane Anesthesia in Pregnant Mice Induces Neurotoxicity in Fetal and Offspring Mice

Each year, over 75,000 pregnant women in the United States undergo anesthesia care. The authors set out to assess the effects of the anesthetic sevoflurane on neurotoxicity in pregnant mice and on learning and memory in fetal and offspring mice. Read more


Early Developmental Exposure to Volatile Anesthetics Causes Behavioral Defects in Caenorhabditis elegans

The authors hypothesized that exposing the nematode (C. elegans) to volatile anesthetics early in life would induce neuron cell death, producing a behavioral defect that would be manifested in adulthood. Read more


Selective Anesthesia-induced Neuroinflammation in Developing Mouse Brain and Cognitive Impairment

The authors have established an animal model with single versus multiple exposures of anesthetic(s) in young versus adult mice, aiming to distinguish the role of different types of anesthesia in cognitive impairment. Read more


Repeated Exposure to Propofol Potentiates Neuroapoptosis and Long-term Behavioral Deficits in Neonatal Rats

The authors investigated the effects of neonatal propofol anesthesia on neuroapoptosis and long-term spatial learning/memory functions. Read more

2012 Archive

October 2012

Experts Work Towards Developing Consensus Regarding Anesthetic Safety in Children

Although the anesthesia community and the FDA agree there are insufficient data to demonstrate a causal link between the use of anesthetics and neurotoxicity in the human pediatric population, the need has grown to communicate accurately to practitioners and parents the current understanding of the risks. On September 10, 2012, the International Anesthesia Research Society (IARS) and the U.S. Food and Drug Administration (FDA) held a SmartTots Scientific Workshop with the goal of developing a consensus statement regarding the safety of anesthetic and sedative drugs administered to infants and young children. Over 60 experts in pediatric medicine and patient safety attended. Read More


Recent Research Articles

SmartTots: A Public-Private Partnership Between the United States Food and Drug Administration (FDA) and the International Anesthesia Research Society (IARS)

A history of the SmartTots public-private partnership between the IARS and FDA is presented. SmartTots was established to raise money for research to better understand the relationship between sedative and anesthetic agents and neurotoxicity in the developing brain. Read More


Propofol at Clinically Relevant Concentrations Increases Neuronal Differentiation But Is Not Toxic to Hippocampal Neural Precursor Cells In Vitro

Propofol in the early postnatal period has been shown to cause brain cell death. One proposed mechanism for cognitive dysfunction after anesthesia is alteration of neural stem cell function and neurogenesis. The authors examined the effect of propofol on neural precursor or stem cells (NPCs) grown in vitro. Read More


General Anesthesia: A Gateway to Modulate Synapse Formation and Neural Plasticity?

Appropriate balance between excitatory and inhibitory neural activity patterns is of utmost importance in the maintenance of neuronal homeostasis. General anesthetic–induced pharmacological interference with this equilibrium results not only in a temporary loss of consciousness but can also initiate long-term changes in brain function. Read More


Anesthetics and the Developing Brain: Time for a Change in Practice? A Pro/Con Debate

Early clinical observations, approximately 60 years ago, raised the possibility of a causal link between anesthesia exposure and CNS dysfunction in young children. However, this issue only gained widespread interest following the publication of experimental data less than 15 years ago. Read More


Upcoming Events

Society for Pediatric Anesthesia’s 2012 International Assembly for Pediatric Anesthesia

October 11-12, 2012, Washington, DC Related Sessions

  • Keynote: IARS Lecture – SmartTots
  • Anesthetics and the Developing Brain: Time for a Change in Practice?

Visit SmartTots at Booth 20!


SNACC 40th Anniversary Annual Meeting

October 11-12, 2012, Washington, DC Related Sessions

  • Poster Session: Neurotoxicity 1

Visit SmartTots at Booth 4!


American Society of Anesthesiologists’ Anesthesiology 2012

October 13-17, 2012, Washington, DC Related Sessions

Visit SmartTots in Concourse A!


American Academy of Pediatrics National Conference & Exhibition

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

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

September 2012

SmartTots-Funded Research Projects

SmartTots is pleased to announce Robert Block, PhD and Caleb Ing, MD as the recipients of our inaugural round of research grants. Dr. Block and Dr. Ing are investigating the existence of a clinical signal suggesting poor neurocognitive outcomes as the result of early exposure to anesthesia. Both recipients received $100,000 to fund their studies. Read More


CaleIngb Ing, MD Columbia University Anesthetic Exposure Duration and Effects on Cognitive and Language Ability Block photographRobert Block, PhD University of Iowa General Anesthesia During Human Infancy and Brain Development IARS Awards $750,000 Grant to Investigate Effect of Anesthetics in Non-Human Primates (NHPs) IARS awarded Ansgar Brambrink, MD, PhD, of Oregon Health & Science University, with a $750,000 research grant to investigate long-term consequences of anesthesia exposure in infant non-human primates (NHPs), an experimental model with high translational relevance to the human condition. Dr. Brambrink’s studies will determine whether negative consequences occur in non-human primates, which should bring the scientific and medical communities closer to translating the animal data to humans. Read More Brambrink1Ansgar Brambrink, MD, PhD Oregon Health & Science University Long-Term Outcome of Single vs. Triple Anesthesia Exposure of Infant Monkeys


Special Thanks!

The Japan Society for Clinical Anesthesia Donates $20,000!

The Japan Society for Clinical Anesthesia (JSCA) has demonstrated its commitment and support of the SmartTots Initiative with a donation of $20,000 for pediatric anesthesia research. Read More


Over $17,000 Raised for SmartTots Research at the IARS 2012 Annual Meeting!

Thank you to all who attended the 2012 Party with a Purpose fundraiser, held at this year’s IARS Annual Meeting in Boston, on May 20, 2012. The event hosted more than 140 guests and raised more than $17,000 for SmartTots research! Thanks again to the event sponsors and donors for their generous contributions! To view photos from this year’s Party with a Purpose, including Dr. Steven Shafer’s escape from a straight jacket, visit the SmartTots Facebook page!


Recent Research Articles

SmartTots Researchers Publish Separate Articles Linking Single Anesthetic Exposure to Poor Neurocognitive Outcomes in Pediatric Patients

Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood?


Clonidine Abolishes the Adverse Effects on Apoptosis and Behavior after Neonatal Ketamine Exposure in Mice

An increasing amount of both experimental and epidemiological data indicates that neonatal anesthesia causes disruption of normal brain development in rodents and primates, as manifested by acute increased apoptosis and long-lasting altered behavior and learning. It is necessary to seek strategies that avoid the possible adverse effects after anesthesia. Read More


Review Article: Neuraxial Analgesia in Neonates and Infants: A Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. Read More


Neonatal Exposure to Sevoflurane Causes Apoptosis and Reduces nNOS Protein Expression in Rat Hippocampus

A growing number of studies have shown that commonly used anesthetic agents may cause neurohistopathological changes and persistent behavioral impairments in the developing brain. The effects of sevoflurane, a widely used substance in pediatric anesthesia, on the developing brain have not been thoroughly analyzed thus far. Read More

March 2012

Current Research

Delayed environmental enrichment reverses sevoflurane-induced memory impairment

Anesthesia given to immature rodents causes cognitive decline, raising the possibility that the same might be true for millions of children undergoing surgical procedures under general anesthesia each year. The authors tested the hypothesis that anesthesia-induced cognitive decline in rats is treatable. Read more


Neurotoxicity and the need for anesthesia in the newborn: Does the emperor have no clothes?

In 2011 nearly half the pediatric papers in Anesthesiology were related to neurotoxicity of general anesthetics to the developing brain. There is continued debate about the clinical relevance of the animal data, and the interpretation of human cohort studies. As we slowly unravel the question of whether or not general anesthetics cause any clinically significant effect on brain development, we should perhaps address some wider-related issues that sometimes go unsaid. Read more


Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia

Authors study the association between exposure to procedures performed under general anesthesia before age 2 years and development of attention-deficit/hyperactivity disorder (ADHD). Read more


Effect of general anesthetics on the developing brain

Studies on rodents and subhuman primates suggest that prolonged exposure to general anesthetics may induce widespread neuronal cell death and neurological sequelae, seriously questioning the safety of pediatric anesthesia. This review presents recent developments in this rapidly emerging field. Read more


Upcoming Events

World Congress of Anesthesiologists

March 25-30, 2012,
 Buenos Aires, Argentina Related Sessions 
• Mechanisms of Perioperative Neurotoxicity • Perioperative Cognitive Dysfunction


International Anesthesia Research Society 2012 Annual Meeting

May 18-21, 2012, Boston, Massachusetts Related Sessions 
• Pediatric Anesthesia Neurotoxicity • Pediatric Anesthesia: Little People with Lots of Problems! • Developmental Neurotoxicity: Are the Narcotics Safe?


Euroanesthesia 2012

June 9-12, 2012, Paris, France Related Sessions • General Anesthesia and the Developing Brain: Is Anything Safe?


Party with a Purpose!

Join your colleagues on Sunday, May 20th as we “Party with a Purpose” at the 2012 Annual Meeting in Boston. This fundraising dinner will help raise awareness of, and funds for, anesthesia research. This exciting event includes a hosted bar (beer/wine), dinner/dessert, live music/dancing as well as an auction featuring stays in Las Vegas and Aruba! Black tie optional. Tickets are $100 each. Visit the event webpage for more information and to purchase your ticket today (advertising and sponsorship opportunities also available).

January 2012

Current Related Research

The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: The importance of free oxygen radicals and mitochondrial integrity

Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reactive oxygen species (ROS), which, if not scavenged in timely fashion, may cause excessive lipid peroxidation and damage of cellular membranes. This study examines whether early exposure to GA results in ROS upregulation and whether mitochondrial protection and ROS scavenging prevent GA-induced pathomorphological and behavioral impairments. Read More


Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain

Exposure of rhesus macaque fetuses for 24 h or neonates for 9 h to ketamine anesthesia causes neuroapoptosis in the developing brain. The current study clarifies the minimum exposure required for and the extent and spatial distribution of ketamine-induced neuroapoptosis in rhesus fetuses and neonates. Read More


Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation

Propofol exposure to neurons during synaptogenesis results in apoptosis, leading to cognitive dysfunction in adulthood. Previous work from the authors’ laboratory showed that isoflurane neurotoxicity occurs through p75 neurotrophin receptor (p75NTR) and subsequent cytoskeleton depolymerization. Given that isoflurane and propofol both suppress neuronal activity, we hypothesized that propofol also induces apoptosis in developing neurons through p75NTRRead More


Protective function of nicotinamide against ketamine-induced apoptotic neurodegeneration in the infant rat brain

During development, anesthetics activate neuroapoptosis and produce damage in the central nervous system that leads to several types of neurological disorders. A single dose of ketamine (40 mg/kg) during synaptogenesis in a 7-day-old rat brain activated the apoptotic cascade and caused extensive neuronal cell death in the forebrain. In this study, we investigated the protective effect of nicotinamide against ketamine-induced apoptotic neurodegeneration. Read More


Effects of metabotropic glutamate receptor 7 allosteric agonist N,N’-dibenzhydrylethane-1,2-diamine dihydrochloride on developmental sevoflurane neurotoxicity: role of extracellular signal-regulated kinase 1 and 2 Mitogen-activated protein kinase signaling pathway

The present study was designed to evaluate the possible neuroprotective effects of metabotropic glutamate receptor (mGluR7) allosteric agonist N,N’-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) on developmental sevoflurane neurotoxicity. Read More


Upcoming Events

EURO-NEURO 2012: 7th International Update on Interdisciplinary Neuroscience

February 16-18, 2012, 
Vienna, Austria Related Sessions 
• Neuroprotection and Neurotoxicity


World Congress of Anesthesiologists

March 25-30, 2012,
 Buenos Aires, Argentina Related Sessions 
• Mechanisms of Perioperative Neurotoxicity • Perioperative Cognitive Dysfunction


International Anesthesia Research Society 2012 Annual Meeting

May 18-21, 2012, Boston, Massachusetts Related Sessions 
• Pediatric Anesthesia Neurotoxicity • Pediatric Anesthesia: Little People with Lots of Problems! • Developmental Neurotoxicity: Are the Narcotics Safe?

2011 Archive

December 2011

SmartTots-Related Research Articles

Nociceptive Stimuli Enhance Anesthetic-Induced Neuroapoptosis in the Rat Developing Brain

Anesthetic-induced neurodegeneration in the developing brain has been well documented. However, the experiments carried out so far do not include surgical conditions. This proof of concept study was designed to investigate the impact of nociceptive stimuli on anesthetic induced neuroapoptosis in the rat developing brain. Read more.


Repeated Administration of Propofol Upregulated the Expression of c-Fos and Cleaved-Caspase-3 Proteins in the Developing Mouse Brain

This study was designed to analyze the relationship between the expression of c-Fos protein and apoptosis in the hippocampus following propofol administration in infant mice. No adequate evaluations have been available as to whether the dosage of propofol to maintain anesthesia could trigger the expression of c-Fos and apoptosis. Read more.


Transient Effects of Anesthetics on Dendritic Spines and Filopodia in the Living Mouse Cortex

Anesthetics are widely used to induce unconsciousness, pain relief, and immobility during surgery. It remains unclear whether the use of anesthetics has significant and long-lasting effects on synapse development and plasticity in the brain. To address this question, the authors examined the formation and elimination of dendritic spines, postsynaptic sites of excitatory synapses, in the developing mouse cortex during and after anesthetic exposure.Read more.


Ketamine and Propofol in Combination Induce Neuroapoptosis and Down-Regulate the Expression of N-Methyl-D-Aspartate Glutamate Receptor NR2B Subunit in Rat Forebrain Culture

Ketamine has always been used in combination with propofol in pediatric patients. This study aimed to investigate whether ketamine or ketamine in combination with propofol induces apoptosis and regulates the expression level of NMDA receptor NR2B subunit in rat forebrain culture. Read more.


Upcoming Events

EURO-NEURO 2012: 7th International Update on Interdisciplinary Neuroscience

February 16-18, 2012 Vienna, Austria Related Sessions • Neuroprotection and Neurotoxicity


World Congress of Anesthesiologists

March 25-30, 2012 Buenos Aires, Argentina Related Sessions • Mechanisms of Perioperative Neurotoxicity • Perioperative Cognitive Dysfunction


Give the Gift of Research

SmartTots is currently reviewing research proposals and will be awarding our first round of research grants early 2012. Show your support this holiday season by donating to the SmartTots research effort. 100% of your gift will support research and is completely tax deductible in the United States! Donate now.

November 2011

Recent SmartTots-Related Research Articles

Anesthetic Neurotoxicity: A Difficult Dragon to Slay

It has become difficult to open an anesthesiology journal without seeing an article about anesthetic neurotoxicity. Most of the work has been done in animals and suggests that harm can come to the developing brain when it is exposed to a broad array of commonly used anesthetic and sedative agents. The critical question, of course, is, does it happen in children? Read more.


The Role of Calcium Dysregulation in Anesthetic-Mediated Neurotoxicity

Increasing evidence suggests that general anesthetics, either volatile or IV, can induce cell death by apoptosis in a concentration- and time-dependent manner in different types of cells, including neurons, in various animal models. Read more.


Anesthetics and Sedatives: Toxic or Protective for the Developing Brain?

Despite our insufficient understanding of the exact molecular mechanisms of general anesthetics and sedatives, every year millions of children are treated with these drugs in a seemingly safe manner. However, increasing evidence particularly from animal studies has suggested the possibility for deleterious effects in pediatric patients. Read more.


Anesthetic-Related Neurotoxicity and the Developing Brain: Shall We Change Practice?

Accumulating experimental evidence together with recent epidemiologic observations suggest that general anesthetics might exert undesirable effects on the immature nervous system. The goal of this review is to highlight basic science issues as well as to critically present experimental data and clinical observations relevant to this possibility. Read more.


News and Events

SmartTots Featured in Anesthesia & Analgesia

The November issue of Anesthesia & Analgesia, now in circulation, highlights current research related to pediatric anesthesia neurotoxicity and the SmartTots research effort. This issue features eight articles, including an editorial from SmartTots Steering Committee Co-Chairs Drs. James Ramsay and Bob Rappaport. Read now.


European Society of Anesthesiologists Establishes European Task Force

SmartTots affiliate, the European Society of Anesthesiologists, is recruiting individuals to serve on their Euro-SmartTots Task Force. Euro-SmartTots is designed to further SmartTots research and fundraising efforts in Europe. Learn more.


World Congress of Anaesthesiologists

March 25-30, 2012 Buenos Aires, Argentina Panel Alert: Mechanisms of Perioperative Neurotoxicity


Every Donation Makes a Difference

SmartTots needs your help to assess the impact of anesthetics on the developing brain. Donate today to support the needed research and SmartTots Executive Board Chair Dr. Michael Roizen will add a matching donation. Your support will help ensure the safety of millions of infants and young children who undergo anesthesia and sedation each year.

October 2011

Recent SmartTots-Related Research

Cognitive and Behavioral Outcomes After Early Exposure to Anesthesia and Surgery

Repeated exposure to anesthesia and surgery before the age of 2 shown to be a significant independent risk factor for the later development of learning disabilities but not the need for educational interventions related to emotion/behavior. Read More


Neurotoxicity of Anesthetic Drugs in the Developing Brain

Anesthesia kills neurons in the brain of infantile animals, including primates, and causes permanent and progressive neurocognitive decline. The anesthesia community and regulatory authorities alike are concerned that is also true in humans. Read More


Neonatal Desflurane Exposure Induces More Robust Neuroapoptosis than Do Isoflurane and Sevoflurane and Impairs Working Memory

In an animal model, neonatal desflurane exposure induced more neuroapoptosis than did sevoflurane or isoflurane and impaired working memory, suggesting that desflurane is more neurotoxic than sevoflurane or isoflurane. Read More


GABAergic Excitotoxicity Injury of the Immature Hippocampal Pyramidal Neurons’ Exposure to Isoflurane

Isoflurane-mediated enhancement of GABA-triggered [Ca2+]i release results from membrane depolarization with subsequent activation of VDCCs and further Ca2+-induced Ca2+ release from the ryanodine-sensitizing Ca2+ store. Read More


General Anesthesia Causes Long-term Impairment of Mitochondrial Morphogenesis and Synaptic Transmission in Developing Rat Brain

Developing mitochondria are exquisitely vulnerable to general anesthesia and may be important early target of anesthesia-induced developmental neurodegeneration. Read More November issue of Anesthesia & Analgesia to feature SmartTots and pediatric anesthesia neurotoxicity. Issue mails end of October.


Coming Up

Society for Pediatric Anesthesia’s 25th Annual Meeting

October 14, 2011 Hyatt McCormick Place, Chicago, Illinois Panel Alert: Anesthesia for the Neonate – Yesterday, Today and Tomorrow: From Paralysis to Toxicity


Anesthesiology 2011 – American Society of Anesthesiologists

October 15-19, 2011 McCormick Place Complex, Chicago, Illinois Panel Alert: Anesthetic Related Neurotoxicity in Children: Research, Regulation and Practice


Request for Applications – Deadline Approaching

The last day to submit a proposal in response to our request for applications is October 21. Studies aimed at investigating whether anesthetics impede brain development are welcome. Read the full RFA and apply now.


Show Your Support

Millions of infants and young children receive anesthesia each year. Without the necessary research data, we have no way of knowing whether these children are at risk for future developmental difficulties. Your donation will help fund research needed to ensure safe anesthetic exposure. Will you show your support by donating today? 100% of your gift will be directly allocated to research, and Dr. Michael Roizen, Chair of our Executive Board, will match your donation with a personal contribution of his own.

September 2011

Safety of Anesthetics Strongly Age Dependent

General anesthesia administered to the developing animal brain depresses much needed neuronal activity and communication resulting in long-lasting cognitive impairment, according to an article published in the August issue of Current Opinion in Anesthesiology. Learn more


Dr. Michael Roizen Takes SmartTots to India

Dr. Michael Roizen, Chair of the SmartTots Executive Board, presented a key session dedicated to pediatric anesthesia neurotoxicity in Bengaluru, India on Saturday, August 27. Anesthesiologists from eight countries convened to hear Dr. Roizen discuss recent outcomes and ongoing research efforts related to the safe use of anesthetics in young children. Read more


Grants and Resources

Request for Applications

We are now accepting research proposals aimed at investigating whether anesthetics impede the normal development of the human brain. Applications accepted now through October 21. Read the full RFA and submit an application


Now Available: Speaker Presentations from Neurotoxicity Panel

Presentations from our Pediatric Anesthesia Neurotoxicity panel held at the IARS 2011 Annual Meeting in Vancouver, Canada are now available for review and download. View speaker presentations


Upcoming Events

Anesthesia for the Neonate – Yesterday, Today and Tomorrow: From Paralysis to Toxicity

October 14, 2011 Society for Pediatric Anesthesia’s 25th Annual Meeting Hyatt McCormick Place, Chicago, Illinois Speakers to discuss laboratory findings related to anesthetic-induced developmental neurotoxicity, whether these findings can be extrapolated to clinical care, and safe alternatives for anesthesia and sedation in neonates.


Anesthetic Related Neurotoxicity in Children: Research, Regulation and Practice

October 15, 2011 Anesthesiology 2011 – American Society of Anesthesiologists McCormick Place Complex, Chicago, Illinois Speakers to highlight current clinical and preclinical research suggesting anesthetic exposure may be toxic to the developing brain and potential changes in practice that may result from ongoing research and public concerns.

August 2011

Translating the animal data

Following the FDA’s Advisory Committee Meeting in March, our Scientific Advisory Board acknowledged insufficient data available to determine whether anesthetics induce neurotoxicity in the developing human brain. We are dedicating our initial research investigations to elucidating whether a clinical signal exists. See our key research questions.


Data links anesthesia & learning disabilities Infants and very young children exposed to anesthesia may experience higher rates of learning disabilities and cognitive difficulties than children who are not exposed to anesthesia according to research and emerging data presented on May 23, during our Pediatric Anesthesia Neurotoxicity panel at the IARS annual meeting in Vancouver, B.C. Read more.


Fundraising campaign in motion

The International Anesthesia Research Society just donated $200,000 and Dr. Mike Roizen committed an annual $50,000 challenge grant, launching our first fundraising campaign. 100% of all individual donations will be directly allocated to research. Will you donate today, and help us achieve Dr. Roizen’s challenge?


Recent Articles

We are committed to keeping you informed. View recent articles in anesthetic neurotoxicity research. Recently published an article or have one in the pipeline? Send us an email and we’ll keep you on our radar.


Our Supporters

We would like to thank our partners for their commitment to ensuring the safety of anesthetics in infants and young children.
American Academy of Pediatrics
Anesthesia & Analgesia
Anesthesia Patient Safety Foundation
American Society of Anesthesiologists
Canadian Anesthesiologists’ Society
International Anesthesia Research Society
Society for Neuroscience and Critical Care in Anesthesiology
Society for Pediatric Anesthesia
Society for Paediatric Anaesthesia in New Zealand and Australia
US Food and Drug Administration