SmartTots Newsletter

Archived Articles

2015 Archive


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

2014 Archive


Research News & Updates

FDA Science Board Meets

The FDA Science Board met on November 19 to review the existing nonclinical and clinical data related to the use and potential toxicity of anesthetics and sedation drugs in the pediatric population.

Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children. 

This paper reviews some of the preclinical background behind anesthesia-related neurotoxicity but focuses mainly on the human studies. It concludes that the human studies performed so far have been unable to confirm the animal data. A single brief anesthetic seems safe in infants. Multiple anesthetic and surgical exposures on the other hand are different, but this may be due to reasons other than the anesthetics.  Read more

Are Caudal Blocks for Pain Control Safe in Children? An Analysis of 18,650 Caudal Blocks from the Pediatric Regional Anesthesia Network (PRAN) Database.

Safety concerns should not be a barrier to the use of caudal blocks in children assuming an appropriate selection of local anesthetic dosage.  Read more

Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice.

These data suggested that sevoflurane induced Tau phosphorylation, glycogen synthase kinase 3β activation, increase in interleukin-6 and reduction in postsynaptic density protein-95 levels in hippocampus of young mice, and cognitive impairment in the mice.  Read more

Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment

These results suggest that Vitamin C attenuated the isoflurane-induced caspase-3 activation and cognitive impairment by inhibiting the isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels.  Read more

Ketamine Affects the Neurogenesis of Rat Fetal Neural Stem Progenitor Cells via the PI3K/Akt-p27 Signaling Pathway.

The inhibition of PI3K/Akt-p27 signaling may be involved in ketamine-induced neurotoxicity in the developing brain, whereas excitatory NMDA receptor activation may reverse these effects.  Read more



FDA Science Board Review: November 19

On November 19, 2014, the FDA Science Board will review the existing nonclinical and clinical data related to the use and potential toxicity of anesthetics and sedation drugs in the pediatric population. 

Consensus Statement and Revision

In December 2012, SmartTots released a Consensus Statement on the Use of Anesthetics and Sedatives in Children to provide guidance to healthcare providers and parents with regard to research findings that suggest anesthetics may be harmful to the developing brain. Consideration of the emerging evidence has prompted a revision of the 2012 statement.  Read more

Research News & Updates

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

Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, pooling of major/minor conditions and major/minor surgeries should be avoided.  Read more

Do we actually need to anesthetize the neonate?

Recurring themes are that neonatal physiology is substantially different from older children, that there are substantial gaps in our understanding of basic pharmacology and physiology, and there is a relative paucity of strong clinical evidence to guide practice.  Read more

Report of the Fourth PANDA Symposium on Anesthesia and Neurodevelopment in Children

The PANDA symposium has become a platform to review current preclinical and clinical data related to anesthetic neurotoxicity, to discuss relevant considerations in study design and approaches to future research among clinicians and researchers, and finally to engage key stakeholders in this controversial public health topic.  Read more

Clinical Research Into Anesthetic Neurotoxicity: Does Anesthesia Cause Neurological Abnormalities in Humans?

Additional preclinical and clinical research efforts are urgently required to address the effects of anesthetic exposure in human brain development.  Read more

Review: effects of anesthetics on brain circuit formation

There is evidence that anesthetics can disrupt brain circuit formation, including effects on neuronal survival and neurogenesis, neurite growth and guidance, formation of synapses, and function of supporting cells.  Read more

Isoflurane Impairs the Capacity of Astrocytes to Support Neuronal Development in a Mouse Dissociated Coculture Model

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

Postoperative Cognitive Function Following General Versus Regional Anesthesia: A Systematic Review

Sixteen studies were included in the final analysis. Three studies showed some difference in cognitive function between regional and general anesthesia, whereas the remaining 13 showed no difference between regional and general anesthesia on postoperative cognitive function.  Read more

Neurodevelopmental Outcomes After Initial Childhood Anesthetic Exposure Between Ages 3 and 10 Years

Decreased motor function was found in children initially exposed after age 3 even after accounting for comorbid illness and injury history.  Read more

Engaging Stakeholders in Research Related to Anesthesia and Neurodevelopment in Children

Clinicians and researchers need to adopt strategies to engage and partner with stakeholders as co-investigators who actively participate in efforts to increase anesthetic safety in children.  Read more

Pediatric Surgeons and Anesthesiologists Expand the Dialogue on the Neurotoxicity Question, Rationale for Early and Delayed Surge

Given recent publications suggesting the potential for neurotoxicity following anesthesia in pediatric patients, physicians, parents, and other stakeholders are now challenged to continue to balance safety with efficacy in caring for children. Read more


Research News & Updates

Cognitive Outcome after Spinal Anesthesia and Surgery During Infancy

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

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

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

Neonatal Anesthesia Neurotoxicity: A Review for Cleft and Craniofacial Surgeons

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

Erythropoietin protects newborn rat against sevoflurane-induced neurotoxicity

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

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

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

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

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

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

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


SmartTots Featured at Canadian Anesthesiologists’ Society Annual Meeting 2014

SmartTots would like to extend a special thank-you to the Canadian Anesthesiologists’ Society, for providing SmartTots with complimentary booth space at the their annual meeting in St. John’s, Newfoundland.  We are grateful for the continued support from our affiliated organizations and their members.

Research News & Updates

Long term neurotoxicity by general anesthetics in infants

A large volume of literature has accumulated in the form of animal and human studies which have implicated general anesthetic drugs like ketamine, propofol, volatile agents, and benzodiazepines in the development of neurodegenerative conditions in later life.  A direct cause effect relationship is yet to be firmly established.  Further research and evidence in this arena is demanded. Read more

Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell-derived Neurons.

These data suggest that (1) human embryonic stem cell-derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in human embryonic stem cell-derived neurons, and (3) the propofol-induced cell death may occur via a signal transducer and activator of transcription 3/miR-21/Sprouty 2-dependent mechanism. Read more

Anesthetic Preconditioning Inhibits Isoflurane-Mediated Apoptosis in the Developing Rat Brain

The ISO-mediated increase in cleaved caspase-3 in the postnatal day 7 rat brain is ameliorated by preconditioning with a brief anesthetic exposure, and differences were not detected in other markers of neuronal injury. Read more

Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats.

Our results indicate that the JNK and p38 pathways, not the ERK pathway, are involved in dexmedetomidine-induced neuroprotection against isoflurane effects. Read more

Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain.

Ketamine caused neuroapoptosis and impaired brain functions in the developing rat brain, which can be effectively attenuated by dexmedetomidine. Dexmedetomidine alone was not neurotoxic to the developing brain. Read more

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats.

Propofol-caused acute increases in corticosterone levels and γ-aminobutyric acid type A receptor-mediated excitation at the time of anesthesia may play mechanistic roles in development of exacerbated endocrine responses to stress and neurobehavioral abnormalities. Read more

Comparison of neurodegeneration and cognitive impairment in neonatal mice exposed to propofol or isoflurane.

Both isoflurane and propofol caused significant apoptosis in the mouse developing brain, with isoflurane being more potent. Isoflurane significantly increased levels of the plasma neurodegenerative biomarker, S100β. However, these neurodegenerative effects of isoflurane and propofol in the developing brain were not associated with effects on inflammation or with cognitive dysfunction in later life. Read more

Repeated Administration of Ketamine can Induce Hippocampal Neurodegeneration and Long-Term Cognitive Impairment via the ROS/HIF-1α Pathway in Developing Rats.

We suggest that ketamine-induced neurodegeneration in neonatal rats, followed by long-term cognitive deficits, might be mediated via the ROS/HIF-1α pathway. Read more

Impact of ketamine on learning and memory function, neuronal apoptosis and its potential association with miR-214 and PTEN in adolescent rats.

Ketamine at a dose of 80 mg/kg in the adolescent rats is able to induce the learning and memory impairment and neurodegeneration, in which the down-regulation of miR-214 and high expression of PTEN protein may be involved. Read more


Successful SmartTots Workshop Held in Washington, DC

A highly productive SmartTots Workshop was held in Washington, DC on June 20.  More than 50 researchers and stakeholders convened to identify a study or series of studies that would inform the future scientific direction and fundraising activities of the SmartTots initiative, and to consider whether modifications to the 2012 Consensus Statement on the Use of Anesthetics and Sedatives in Children are warranted in light of the additional research findings over the past 18 months.  Significant progress was made toward both objectives.

The workshop commenced with a charge from the SmartTots Steering Committee Co-Chairs, Dr. Santhanam Suresh of Lurie Children’s Hospital in Chicago and Dr. Bob Rappaport, Director of the Division of Anesthesia, Analgesia, and Addiction Products in the FDA Center for Drug Evaluation and Research, followed by presentations from 11 investigators who reported on their studies and findings to date.  The participants then split into two breakout sessions, with one discussing the needed studies while the other considered the Consensus Statement.  The group reconvened in a plenary session to hear reports from the breakout groups and discuss their work.

A complete report on the workshop outcomes will be included in a future SmartTots e-Newsletter.


Research News & Updates

Effect of General Anesthesia in Infancy on Long-Term Recognition Memory in Humans and Rats

Twenty eight children ages 6-11 who had undergone a procedure requiring general anesthesia before age 1 were compared to 28 age- and gender-matched children who had not undergone anesthesia.  In parallel, thirty-three 7-day-old rats were randomized to receive anesthesia or sham anesthesia.  Our findings suggest that general anesthesia in infancy impairs recollection later in life in humans and rats. In rats, this effect is independent of underlying disease or tissue injury. Read more

General anaesthetics and the developing brain: an overview.

Anaesthetic exposure during a critical period of neuronal development can have significant impact on neurocognitive function later in life. Until proven otherwise, it can be recommended to keep anaesthesia and surgery as short as possible, to use short-acting drugs and/or a combination of general anaesthesia and multimodal pain therapy including systemic analgesics, and local or regional anaesthesia, to reduce the overall drug dosage.  Read more

The Neonatologist’s Role in Pediatric Anesthesia Neurotoxicity

A fundamental assumption of anesthetic practice has always been that the effects of sedatives and anesthetic agents resolve when these drugs are metabolized and excreted from the body. This core assumption has recently been challenged by compelling evidence in animals. In this context, we welcome the publication by Morriss et al in this issue of the journal. However, as is true with every human neurotoxicity study to date, their work raises as many questions as it answers. Read more

Cognitive Outcome after Spinal Anesthesia and Surgery During Infancy

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

Repeated Exposure to Anesthetic Ketamine Can Negatively Impact Neurodevelopment in Infants: A Prospective Preliminary Clinical Study.

Our results suggest that 3 or more exposures to anesthetic ketamine have the potential to adversely affect neurodevelopment in infants.  Read more

The role of miR-21 in propofol-induced neurotoxicity in developing human neurons (1093.2)

In this study, we assessed the effects of propofol on human embryonic stem cell (hESC)-derived neurons and the role of microRNAs (miRs) in the toxicity observed. hESCs were differentiated into neurons following a four-step differentiation protocol. Exposure to 20 µg/mL propofol for 6 hours induced significant cell death in the hESC-derived neurons and downregulated several microRNAs, including miR-21. Overexpression of miR-21 significantly attenuated the increase in cell death following propofol administration. Read more

Inhibition of aberrant cyclin-dependent kinase 5 activity attenuates isoflurane neurotoxicity in the developing brain

Our results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain. Read more

Involvement of RAGE in isoflurane-induced neuronal apoptosis

Isoflurane has been reported to cause neurotoxicity and neurocognitive impairments in neonatal rats. Previous reports suggest elevated levels of S100B after anesthesia and brain trauma. The receptor for advanced glycation end products (RAGE) is the only known cell surface receptor for S100B and expressed in the brain. RAGE activation in neurons has also been shown to lead to apoptosis and neurodegeneration. Our research demonstrates that RAGE may be involved in the neuronal apoptosis induced by isoflurane. Read more

The role of miR-124 in modulating hippocampal neurotoxicity induced by ketamine anesthesia

Our study demonstrated that miR-124 played an important role in regulating ketamine induced hippocampal neurodegeneration. Inhibiting miR-124 may provide a molecular target to improve memory performance in both human and animals suffering from over-anesthetic related neurotoxicity. Read more

Sevoflurane in combination with propofol, not thiopental, induces a more robust neuroapoptosis than sevoflurane alone in the neonatal mouse brain

Sevoflurane alone can induce neuronal apoptosis, and this effect is enhanced by propofol. Thiopental did not exacerbate the neurotoxicity of sevoflurane. There is the possibility that the combination of sevoflurane and propofol is a more harmful anesthetic technique than sevoflurane alone in pediatric patients. Read More

Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring.

Data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits.Read more

Propofol anesthesia induces proapoptotic tumor necrosis factor-α and pro-nerve growth factor signaling and prosurvival Akt and XIAP expression in neonatal rat brain

These results show that different brain structures respond to propofol anesthesia with a time- and duration-of-exposure-dependent increase in proapoptotic signaling and with concomitant increases in activities of prosurvival proteins. We hypothesized that the fine balance between these opposing processes sustains homeostasis in the immature rat brain and prevents unnecessary damage after exposure to an injurious stimulus. The existence of this highly regulated process provides a time frame for potential therapeutic intervention directed toward suppressing the deleterious component of propofol anesthesia. Read more

SmartTots Workshop

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

Open to all interested professionals. No registration fee.

Workshop Agenda:

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

May 2014

Mark your calendar!

SmartTots Workshop

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

Open to all interested professionals. No registration fee.

Workshop Objectives:

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

Please contact Rebekah Davies, IARS Program Manager for more information or to register for the workshop. [email protected]   415-296-6905

Research News & Updates

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

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

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

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

Anesthetic neurotoxicity

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

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

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

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

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

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

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

Basic aspects of the potential toxicity of anesthetic drugs

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

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

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

Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains

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

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

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

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

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

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

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

Neuroprotective gases–fantasy or reality for clinical use?

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

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

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


March 2014

Mark your calendar!

SmartTots Workshop

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

Open to all interested professionals. No registration fee.

Workshop Agenda:

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

Please contact Rebekah Davies, IARS Program Manager for more information or to register for the workshop. [email protected]   415-296-6915

Research News & Updates

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

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

 Anesthesia considerations in pediatric glaucoma management

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

 Adverse effect of inhalational anesthetics on the developing brain

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 Modeling anesthetic developmental neurotoxicity using human stem cells.

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

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

Caleb Ing, MD
Columbia University

Anesthetic Exposure Duration and Effects on Cognitive and Language Ability

Robert Block, PhD
University of Iowa

General Anesthesia During Human Infancy and Brain Development

IARS Awards $750,000 Grant to Investigate Effect of Anesthetics in Non-Human Primates (NHPs)

IARS awarded Ansgar Brambrink, MD, PhD, of Oregon Health & Science University, with a $750,000 research grant to investigate long-term consequences of anesthesia exposure in infant non-human primates (NHPs), an experimental model with high translational relevance to the human condition. Dr. Brambrink’s studies will determine whether negative consequences occur in non-human primates, which should bring the scientific and medical communities closer to translating the animal data to humans. Read More

Ansgar Brambrink, MD, PhD
Oregon Health & Science University

Long-Term Outcome of Single vs. Triple Anesthesia Exposure of Infant Monkeys

Special Thanks!

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

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

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

Thank you to all who attended the 2012 Party with a Purpose fundraiser, held at this year’s IARS Annual Meeting in Boston, on May 20, 2012. The event hosted more than 140 guests and raised more than $17,000 for SmartTots research!

Thanks again to the event sponsors and donors for their generous contributions! To view photos from this year’s Party with a Purpose, including Dr. Steven Shafer’s escape from a straight jacket, visit the SmartTots Facebook page!

Recent Research Articles

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

Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia

Are Anesthesia and Surgery during Infancy Associated with Altered Academic Performance during Childhood?

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

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

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

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

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

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

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?

2013 Archive


SmartTots Featured at Anesthesiology 2013

Special thank you to ASA, SNACC, and SPA!

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


Research News & Updates

A systematic review and quantitative analysis of neurocognitive outcomes in children with four chronic illnesses.

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


Neurotoxicity of general anesthetics in childhood: does anesthesia leave its mark on premature babies, newborns and infants?

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


SmartTots Funds $400,000 for Pediatric Anesthesia Research

SmartTots is dedicated to funding research that will help determine if any particular anesthetic or sedative drugs pose hazards to young children, design the safest anesthetic and sedative regimes, and potentially foster the development of new practice guidelines and anesthetic drugs. In support of this goal, two research grants for $200,000 each paid over two years were recently awarded to:

Dr. Lena Sun, Columbia University Medical Center in support of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Study

Dr. Jeffrey Sall, University of California San Francisco in support ofRecognition Memory Following Early Childhood Anesthesia

Click here to view the full media release regarding the 2013/2014 grant awardees.

Research News & Updates

FDA Consumer Update Released: Anesthesia: Is it Safe for Young Brains?
When infants or young children need surgery, does anesthesia affect their developing brains?

With more than 1 million children under age 4 requiring anesthesia for surgery in the United States each year, the Food and Drug Administration (FDA) and other health organizations are working together to answer this question. Read more

Neonatal sevoflurane anesthesia induces long-term memory impairment and decreases hippocampal PSD-95 expression without neuronal loss

Volatile anesthetics are widely used in the clinic, and sevoflurane is the most prevalent volatile anesthetic in pediatric anesthesia. Recent findings question the potential risks of volatile anesthetics on brain development. Evidence suggests that sevoflurane may cause neuronal deficiency. This study investigates the long-term effect of sevoflurane in the developing brain. Read more

Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain

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

Ketamine as anesthetics can damage children’s learning and memory ability

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

Characterization and Quantification of Isoflurane-Induced Developmental Apoptotic Cell Death in Mouse Cerebral Cortex

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


Now Accepting Applications: SmartTots 2013 Research Grants

SmartTots is now accepting applications aimed at investigating whether anesthetics/sedatives are neurotoxic and/or impede the normal development of the human brain.

Projects should focus on whether neonatal anesthetic exposure in humans impairs brain development resulting in persistent detrimental effects on cognition or behavior. Studies aimed at identifying either specific anesthetic techniques that do not produce neurotoxic effects or interventions to ameliorate damage will also be considered.

Deadline to apply is April 12, 2013. Get started on your application.

IARS 2013 Annual Meeting

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

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

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

Recent Literature

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

Dual Effects of Isoflurane on Proliferation, Differentiation, and Survival in Human Neuroprogenitor Cells

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

Prognostic Study of Sevoflurane-Based General Anesthesia on Cognitive Function in Children

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


Request for Applications Update

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

Recent Literature

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

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

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

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

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

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

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

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

Perioperative Cent

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