Research and GrantsResearch Priorities | Grants | SmartTots Funded Studies | Related Research Projects
Anesthesia Use in Children: Concerns and the Need for Research
For more than 20 years, researchers have studied the effects of anesthetics on the nervous systems of developing animals. This research continues to demonstrate that exposure to some anesthetics and sedatives cause memory and learning difficulties and other harmful changes in the central nervous systems of some laboratory animals. Currently, inadequate data exist to prove or disprove whether similar effects occur in children. SmartTots launched to address this gap in knowledge, to facilitate and support studies of existing anesthetic drugs and their effects on childhood development, as well as the impact of drug type, dosage amounts and number of exposures. Information from these research studies will help to determine if particular anesthetic drugs pose hazards to young children, to design the safest anesthetic regimens (dose and duration), and potentially foster the development of new anesthetic drugs. To date, ongoing research results are not yet conclusive. However, there have been scientific advances and important pieces to the puzzle are potentially bringing investigators closer to an answer. Recent, emerging research suggests that a single anesthetic exposure of up to 1 hour may not cause measurable abnormalities later in life. More research is needed and SmartTots seeks to support well controlled clinical studies that will ultimately yield definitive answers.
Insufficient human data currently exist to determine whether anesthetics induce neurotoxicity in the developing brain. Current research is focused on determining whether volatile anesthetics administered during periods of rapid brain growth are neurotoxic to the developing human brain, and whether they cause long-term difficulties in learning and behavior. Thus far, implicated anesthetic agents include NMDA receptor antagonists, such as ketamine, and GABA agonists, such as sevoflurane.
View the 2023 IARS Annual Meeting Posters/Abstracts relating to Pediatric Anesthetic Neurotoxicity
Click the linked title to read the abstract.
Title: Neonatally sevoflurane-exposed and unexposed male rat cagemates affect each other’s neurodevelopmental phenotypes
Presenting author: Lingsha Ju
Additional Authors: Anatoly Martynyuk, Timothy Morey, Nikolaus Gravenstein, Barry Setlow, Christoph Seubert, Terrie Vasilopoulos
Title: Alterations in Amygdala Functional Connectivity in Juvenile Non-Human Primates 2 Years after Anesthesia Exposure during Infancy.
Presenting author: Viola Neudecker
Additional Authors: Jose Perez-Zhogbi, Oscar Miranda-Dominguez, Katie Schenning, Lauren Martin, Gregory Dissen, Damien Fair
Title: Isoflurane inhibits synaptic calcium reuptake in mouse neurons in an ATP-dependent manner.
Presenting Author: Sangwook Jung
Additional Authors: Phil Morgan, Beatrice Predoi, Jan-Marino Ramirez, Margaret Sedensky
Title: Behavioral and neuropsychological outcomes in children after exposure to labor epidural analgesia
Presenting Author: Oliver Isik
Additional Authors: Shaqif Junaid, Ling Guo, Deven Lackraj, Ruth Landau, Caleb Miles, Craig Pennell, Britta von Ungern Sternberg, Andrew Whitehouse, Guohua Li, Caleb Ing
Grants and Funded Studies
Jimcy Platholi, MS, PhD – $170,000
Weill Medical College of Cornell University
Role of mossy fiber terminals in early anesthesia neurotoxicity
Genetic polymorphisms increase susceptibility for neurocognitive disorders following anesthesia and surgery, but it is unclear whether or how neuronal dysfunction plays a role in these cognitive deficits. This knowledge is critical to assessing the risk of necessary medical procedures that require anesthesia, particularly in vulnerable populations such as juveniles. General anesthetics modulate synaptic transmission with neurotransmitter-type specificity that may be developmental stage-dependent. This project aims to identify the mechanisms underlying an early window of susceptibility for anesthesia exposure associated with altering neuronal activity in later life. Extension of these studies into single nucleotide polymorphisms that alter neurotransmission during development will further define the role of human genetic variation in early anesthetic sensitivity.
Peter Szmuk, MD – $139,000
UT Southwestern Medical Center
Neurodevelopmental outcome after standard dose sevoflurane versus low-dose
Short anesthesia in infants does not appear to be neurotoxic, but less is known about the effect of longer or multiple anesthetics. This project supports a Phase III, randomized active controlled, parallel group, assessor blinded, multicenter, of the international trial (TREX trial) by comparing the neurodevelopmental outcome after standard dose sevoflurane versus a combination of low-dose sevoflurane, dexmedetomidine and remifentanil anesthesia) in young children having anesthesia expected to last 2 hours or longer. Trial results will provide evidence on the effect of over 2 hours anesthesia on the developing brain and a possible alternative, non-neurotoxic anesthetic regimen for this age group. If no difference is found, the results can provide reassurance for millions of children, their surgeons, and anesthetists.
Lena Sun, MD – $200,000 Grant
Columbia University Medical Center
Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Study
Dr. Lena S. Sun, E.M. Papper Professor of Pediatric Anesthesiology, Professor of Anesthesiology & Pediatrics and Chief of Division of Pediatric Anesthesiology at Columbia University Medical Center, leads the effort as the Principal Investigator of the multi-site PANDA study. PANDA was designed to examine the effects of a single episode of early childhood anesthesia exposure before age 3 years on long-term neurocognitive function and behavior in healthy children. The study is providing the first set of neurocognitive and behavior data in healthy children prospectively collected and directly assessed. The aim is to provide the needed evidence for informed discussions with providers and parents as well as guidance for clinical decision-making.
By mid-2016 the study was complete. The study ultimately included 105 healthy children who underwent surgical repair of inguinal hernia—one of the most common operations of early childhood. IQ scores and secondary neurodevelopmental outcomes, including memory, learning, processing speed, visuospatial function, attention, executive function, language, and behavior, were assessed when the children were between the ages of 8 and 15, allowing enough time after exposure to anesthesia for any impairments to emerge. Outcomes for each child were compared with those of a healthy, biologically related sibling of a similar age who was not exposed to anesthesia. Dr. Sun and her team found that there was no statistically significant difference in IQ scores between the children who were exposed to anesthesia and siblings who were not. However, Dr. Sun stated that while this is good news, there are still important questions unanswered. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.
Jeffrey Sall, PhD, MD – $200,000 Grant
University of California San Francisco
Recognition Memory Following Early Childhood Anesthesia
Dr. Jeffrey Sall, Associate Professor at UCSF School of Medicine, Department of Anesthesia and Perioperative Care, is utilizing the SmartTots grant funding to conduct a research study which is examining the limits or boundary conditions of early childhood anesthesia exposure that lead to cognitive deficits. This project will determine how the duration of anesthesia exposure and the age of the child at the time of exposure affect recognition memory deficits.
During 2015 the study faced a few logistical hurdles but still managed to complete more than 50% of its stated goals, actively partnering with academic centers around the state to recruit and test subjects. During 2016, with the delays behind them, the project was up and running well again and continuing to accrue subjects. Ultimately the results will provide guidance to clinicians and parents when deciding to perform certain procedures and will give future researchers an important outcome measure that is easily testable.
General Anesthesia During Human Infancy and Brain Development
Dr. Block aimed to evaluate the hypothesis that exposure to general anesthesia and surgery during infancy affects brain and cognitive development as reflected in measures of brain tissue volume and composition and white matter integrity, memory-related regional brain activation, and cognitive test performance. Adolescents who were exposed to anesthesia during infancy are compared to unexposed, but otherwise matched, control subjects. Patients will have been exposed to anesthesia during operations that would not normally, in themselves, be associated with subsequent central nervous system problems or risk factors; and both patients and controls will be individuals in whom no such problems or risk factors during infancy can be identified.
By the middle of 2014, Dr. Block’s study analysis found that there were lower white matter volumes and diminished white matter integrity in patients, relative to controls. He also reported finding trends toward differences in brain activity associated with long-term memory and working memory processes in patients, relative to controls. Dr. Block intends to complete the analyses of the present study, publish the results, and seek funding from NIH for a substantially larger-scale study to replicate and extend the results. His new research would involve studying more patients with a broader age range of exposure to anesthesia and comparing patients who were exposed for more vs. less invasive procedures, in addition to unexposed controls.
Caleb Ing, MD – $100,000 Grant
Columbia University Medical Center, New York, New York
Anesthetic Exposure Duration and Effects on Cognitive and Language Ability
Dr. Ing and colleagues are conducting research to determine the relationship between anesthetic exposure before the age of three and long-term neurocognitive deficits using a battery of directly administered neuropsychological assessments. The results of this study will help determine the association between anesthetic exposure and long-term deficits. This will be a critical piece of information that will help parents and physicians weigh the risks and benefits of exposure to anesthesia and whether to delay certain types of elective surgery.
As of April 2016, Dr. Ing and team reported two important research findings, they determined that in their cohort, specific neuropsychological outcome measures related to language and abstract reasoning were able to determine differences in children exposed to anesthesia, while academic achievement tests could not. His team was also able to determine that initial exposure to anesthesia after age 3 had no measurable effects on language and abstract reasoning, suggesting that there may be distinct windows of vulnerability for different neurodevelopmental domains in children. An article published in the Journal of Neurosurgical Anesthesiology highlights their most recent findings. The article also discusses a potential neurodevelopmental phenotype that should be examined in children exposed to anesthesia and also describes the utility of a statistical technique called latent class analysis in analyzing neuropsychological outcomes.
Related Research Projects
Pediatric Anesthesia NeuroDevelopment Assessment (PANDA Study)
The PANDA Study used a sibling-matched cohort design to test the hypothesis that a single exposure to general anesthesia in healthy children younger than age 3 was associated with, at ages 8 to 15, an increased risk of impaired cognitive function (IQ) as the primary outcome and abnormal domain-specific neurocognitive functions and behavior as secondary outcomes. The PANDA Study found among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, that there were no statistically significant differences in IQ scores in later childhood.
Mayo Clinic Research – Mayo Safety in Kids, (MASK Study)
This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 years is associated with adverse neurodevelopmental outcomes. The researchers found that anesthesia exposure before age 3 years was not associated with deficits in the primary outcome of general intelligence. Secondary outcomes suggested the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that are associated with behavioral and learning difficulties.
General Anesthesia compared to Spinal anesthesia (GAS study)
This trial included more than 700 children undergoing inguinal hernia repair during early life who were randomized to either sevoflurane-based general or awake-spinal anesthesia. Both the primary and secondary outcomes of the study demonstrated no association between 1 h of sevoflurane anesthesia in early life and cognitive composite scores at the age 2 years or full-scale intelligence quotient from the Wechsler Preschool and Primary Scale of Intelligence test at the age of 5 years when compared to spinal anesthesia.
Ansgar Brambrink, MD, PhD New York Presbyterian/Columbia University Medical Center
Project: Long-Term Outcome of Single vs. Triple Anesthesia Exposure of Infant Monkeys. At the outset of this study, Dr. Brambrink utilized a newly established infant non-human primate (NHP) model to simulate the human condition of general anesthesia in a highly controlled environment. This project, initially begun by a team of expert neuroscientists at the Oregon National Primate Research Center, relocated in 2016 to the Department of Anesthesiology at Columbia University College of Physicians & Surgeons. The new team of investigators continue to study the long-term functional and morphologic consequences of single vs. triple anesthesia exposure of infant NHPs. Dr. Brambrink’s study is supported by the IARS Frontiers in Anesthesia Research.
- Does inflammation mediate behavioural alterations in anaesthesia-induced developmental neurotoxicity?
- Infant isoflurane exposure affects social behaviours, but does not impair specific cognitive domains in juvenile non-human primates
- Recent advances in understanding cognitive and behavioural alterations after early-in-life anaesthesia exposure and new mitigation/alternative strategies in preclinical studies
- Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain
- Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain
National Center for Toxicological Research (NCTR)
FDA’s National Center for Toxicological Research (NCTR) is conducting non-clinical studies in both rodents and nonhuman primates to assess: 1) the mechanisms underlying the neurotoxicity associated with clinically-relevant general anesthetics such as ketamine, nitrous oxide, and isoflurane; 2) long-term cognitive deficits related to developmental exposure to these agents; 3) strategies to prevent or ameliorate the adverse effects of anesthesia; and 4) the utility of PET imaging approaches to assist in the non-invasive monitoring of the location, severity, and time course of neurotoxic events associated with general anesthesia; it is hoped that such approaches will translate to use in humans.
- Regions of the basal ganglia and primary olfactory system are most sensitive to neurodegeneration after extended sevoflurane anesthesia in the perinatal rat
- Acetyl-l-carnitine does not prevent neurodegeneration in a rodent model of prolonged neonatal anesthesia
- Sevoflurane exposure has minimal effect on cognitive function and does not alter microglial activation in adult monkeys
- Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys
- Ketamine-Induced Neuronal Damage and Altered N-methyl-D-aspartate (NMDA) Receptor Function in Rat Primary Forebrain Culture