Anaesthetic Neurotoxicity In Children Research Articles

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward.

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Anesthetic Neurotoxicity in Children

The clinical pediatric anesthesiology community has been greatly affected by a growing body of research suggesting that sedative drugs and anesthetic agents may have long lasting detrimental neurocognitive effects in children. Various animal models have indicated apoptotic brain cell death and neurocognitive impairment following anesthetic exposure in early life. Although these studies cannot be directly extrapolated to anesthesia in children, parents and governmental regulatory agencies have been paying attention nonetheless. Adding to the evidence are a number of human epidemiologic studies that have documented neurologic deficits and cognitive decline following early anesthetic exposure. 1-4 Clinical studies in children exposed to general anesthesia have assessed outcome measures including academic performance or school readiness, validated neuropsychologic testing, and educational interventions for neurodevelopmental or behavioral problems.

Anesthetic Neurotoxicity in Children

The clinical pediatric anesthesiology community has been greatly affected by a growing body of research suggesting that sedative drugs and anesthetic agents may have long lasting detrimental neurocognitive effects in children. Various animal models have indicated apoptotic brain cell death and neurocognitive impairment following anesthetic exposure in early life. Although these studies cannot be directly extrapolated to anesthesia in children, parents and governmental regulatory agencies have been paying attention nonetheless. Adding to the evidence are a number of human epidemiologic studies that have documented neurologic deficits and cognitive decline following early anesthetic exposure. 1-4 Clinical studies in children exposed to general anesthesia have assessed outcome measures including academic performance or school readiness, validated neuropsychologic testing, and educational interventions for neurodevelopmental or behavioral problems.

A Summary of Preclinical Poster Presentations at the Sixth Biennial Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Symposium.

The potential for long-term neurotoxic effects of anesthetics on the developing human brain has led to intensified research in this area. To date, the human evidence has been inconclusive, but a large body of animal evidence continues to demonstrate cause for concern. On April 14 and 15, 2018 the sixth biennial Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA) study symposium was held at Morgan Stanley Children's Hospital of New York. This symposium brought together clinicians and researchers and served as a platform to review preclinical and clinical data related to anesthesia and neurotoxicity in developing brains. The program participants included many active investigators in the field of anesthesia neurotoxicity as well as stakeholders from different backgrounds with the common interest of potential anesthetic neurotoxicity in children. The moderated poster session included presentations of preclinical animal research studies. These studies focused on defining the anesthetic-induced neurotoxicity phenotype, understanding the mechanism of injury and discovering potential inhibitors of neurotoxic effects.

Report on the Fifth PANDA Symposium on "Anesthesia and Neurodevelopment in Children".

On April 16 and 17, 2016, the Pediatric Anesthesia and Neurodevelopment Assessment (PANDA) study held its fifth biennial symposium at the Morgan Stanley Children's Hospital of New York. The PANDA symposium has served as a key forum for clinicians, researchers, and other major stakeholders to gather and review the current state of preclinical and clinical research related to anesthetic neurotoxicity in children. Goals of the meeting included assessing how current knowledge has translated and impacted clinical care of patients who may be at risk, and future directions for research and policy. The program participants represented a diverse group with a shared concern of potential anesthetic neurotoxicity in children. It included clinicians, preclinical and clinical researchers as well as representatives from government organizations (FDA [Food and Drug Administration] and National Institutes of Health). A total of 135 attended the symposium.

Neuronal apoptosis of the developing brain: Influence of anesthetics

Surgeries and multiple procedures are undertaken on millions of children all over the world which involves exposure of these children to anesthetics during the stage of brain development. There is an increasing concern regarding the risk of anaesthetic neurotoxicity in children. Evidence has shown that exposure to all commonly used anaesthetics and sedatives can cause neurodegeneration in the developing brain with the possible exception of α 2-adrenergic agonists. Anaesthetic effects on the brain during its growth spurt can initiate a cascade of alterations in neurodevelopment which have been detected structurally or functionally in preclinical experiments. The studies are ongoing to gather clinical evidence.

Anesthesia and Apoptosis in the Developing Brain: An Update

There is an increasing concern regarding the risk of anaesthetic neurotoxicity in children. Numerous animal and in vitro studies have demonstrated that general anaesthetics cause a variety of potentially harmful effects on the developing brain. An increased level of neuronal apoptosis is one such effect. In some studies, exposed animals have experienced long-lasting neurobehavioural changes. These effects occur at very specific stages of development and are dose-dependent. There are several plausible mechanisms for these deleterious effects; however, the exact mechanism remains unclear. Most importantly, histological and behavioral effects have been demonstrated in non-human primates. Human research evaluating the long-term effects of anaesthesia on brain development is limited and, to date, has been limited to retrospective observational cohort studies. The results of these studies have not been consistent, with some demonstrating an association between surgery and adverse neurobehavioral outcome and others showing no association. Furthermore, these cohort studies have numerous weaknesses and limitations. An ongoing randomized clinical trial aims to provide clear evidence regarding the clinical safety of anesthetics up to 1 h in neonates and older children.

Feasibility and Pilot Study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Project

Animal studies have documented that exposure of the developing brain to commonly used anesthetic agents induces neurotoxicity and late abnormal neurobehavioral functions as adults. Results from clinical studies have all been analyzed using existing data sets, and these studies produced inconsistent results. To provide more definitive evidence to address the clinical relevance of anesthetic neurotoxicity in children, an interdisciplinary team of investigators designed and developed the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. We present pilot study results in 28 sibling pairs recruited and tested at the Columbia University Medical Center (CUMC) and Children's Hospital of Boston (CHB) for the PANDA project. The PANDA project uses an ambidirectional cohort design. We performed prospective neuropsychological assessment in 28 exposed-unexposed sibling pairs from 6 to 11 years of age. The exposed siblings were ASA 1 or 2 and had received a single episode of anesthesia for inguinal hernia repair before the age of 36 months and the unexposed siblings had no anesthesia before the age of 36 months. All the sibling pairs were English speaking and were 36 weeks of gestational age or older. Each sibling pair underwent a direct testing using the Wechsler Abbreviated Scale of Intelligence (WASI) and the NEuroPSYchological Assessment, second edition (NEPSY II), and the parents completed questionnaires related to behavior using CBCL and Conners rating. Data are presented as means±SD. We conducted descriptive analyses of the demographic data. We compared both the exposed and the unexposed sibling groups on WASI and NEPSY II, and total and T scores from CBCL and Conners rating were analyzed as continuous data using the paired t test between the two groups. A P<0.05 was considered significant. After the Institutional Review Board approval for the study at both CUMC and CHB, the full PANDA study protocol was implemented to perform a pilot feasibility study. Our success rate was 96.7% in obtaining detailed medical and anesthesia records in our historical cohort. The scores for verbal IQ (exposed=106.1±16.3, unexposed=109.2±17.9), performance IQ (exposed=109.1±16.0, unexposed=113.9±15.9), and full IQ (exposed=108.2±14.0, unexposed=112.8±16.8) were comparable between the siblings. There were no differences between the two groups in T scores for any of the NEPSY II subdomains, CBCL, or Conners rating. An abstraction protocol with web-based electronic data capture forms also was developed in conjunction with the International Center for Health Outcomes and Innovation Research (InCHOIR). The pilot study provided useful information for feasibility to recruit the sample size and to obtain relevant clinical data. For the final study protocol, both the neuropsychological battery and the age range for testing were revised. Our results confirmed the feasibility of our study approach and yielded pilot data from neuropsychological testing.

Anesthetic Neurotoxicity

Anesthetic Neurotoxicity

Early childhood general anaesthesia exposure and neurocognitive development

A great deal of concern has recently arisen regarding the safety of anaesthesia in infants and children. There is mounting and convincing preclinical evidence in rodents and non-human primates that anaesthetics in common clinical use are neurotoxic to the developing brain in vitro and cause long-term neurobehavioural abnormalities in vivo. An estimated 6 million children (including 1.5 million infants) undergo surgery and anaesthesia each year in the USA alone, so the clinical relevance of anaesthetic neurotoxicity is an urgent matter of public health. Clinical studies that have been conducted on the long-term neurodevelopmental effects of anaesthetic agents in infants and children are retrospective analyses of existing data. Two large-scale clinical studies are currently underway to further address this issue. The PANDA study is a large-scale, multisite, ambi-directional sibling-matched cohort study in the USA. The aim of this study is to examine the neurodevelopmental effects of exposure to general anaesthesia during inguinal hernia surgery before 36 months of age. Another large-scale study is the GAS study, which will compare the neurodevelopmental outcome between two anaesthetic techniques, general sevoflurane anaesthesia and regional anaesthesia, in infants undergoing inguinal hernia repair. These study results should contribute significant information related to anaesthetic neurotoxicity in children.