General anaesthesia during infancy reduces white matter micro-organisation in developing rhesus monkeys

Young, Jeffrey T.; Vlasova, Roza; Howell, Brittany R.; Knickmeyer, Rebecca; Morin, Elyse; Kuitchoua, Kaela I.; Lubach, Gabriele R.; Noel, Jean; Hu, Xiaoping; Shi, Yundi; Caudill, Gibson; Alexander, Andrew L.; Niethammer, Marc; Paule, Merle G.; Coe, Christopher L.; Sánchez, Mar M.; Styner, Martin

doi:10.1016/j.bja.2020.12.029

Cited by 18 publications

(14 citation statements)

References 40 publications

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“…More significant data can be obtained from juvenile non-human primate (NHP) models, among which rhesus macaques are most commonly applied, regarding their resemblance to humans in physiology, neuroanatomy, development, cognition, and behavior, allow for adequate monitoring of physiological parameters, and use of anesthetic equipment and techniques similar to those used for human children, augmenting the reliability of evidence, because it is possible that the adverse impacts attributed to GA do not occur when physiological parameters are monitored and controlled more effectively (Phillips et al, 2014 ). Extensive negative outcomes have been adopted and detected in NHP models to measure the impairment of the nervous system, ranging from neuronal or oligodendrocyte apoptosis response, cognition, and behavior to MRI results (Paule et al, 2011 ; Brambrink et al, 2012 ; Creeley et al, 2013 ; Raper et al, 2015 , 2018 ; Alvarado et al, 2017 ; Coleman et al, 2017 ; Schenning et al, 2017 ; Talpos et al, 2019 ; Neudecker et al, 2021 ; Young et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

General anesthesia in children and long-term neurodevelopmental deficits: A systematic review

Xiao

Yang

et al. 2022

Front. Mol. Neurosci.

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BackgroundMillions of children experienced surgery procedures requiring general anesthesia (GA). Any potential neurodevelopmental risks of pediatric anesthesia can be a serious public health issue. Various animal studies have provided evidence that commonly used GA induced a variety of morphofunctional alterations in the developing brain of juvenile animals.MethodsWe conducted a systematic review to provide a brief overview of preclinical studies and summarize the existing clinical studies. Comprehensive literature searches of PubMed, EMBASE, CINAHL, OVID Medline, Web of Science, and the Cochrane Library were conducted using the relevant search terms “general anesthesia,” “neurocognitive outcome,” and “children.” We included studies investigating children who were exposed to single or multiple GA before 18, with long-term neurodevelopment outcomes evaluated after the exposure(s).ResultsSeventy-two clinical studies originating from 18 different countries published from 2000 to 2022 are included in this review, most of which are retrospective studies (n = 58). Two-thirds of studies (n = 48) provide evidence of negative neurocognitive effects after GA exposure in children. Neurodevelopmental outcomes are categorized into six domains: academics/achievement, cognition, development/behavior, diagnosis, brain studies, and others. Most studies focusing on children <7 years detected adverse neurocognitive effects following GA exposure, but not all studies consistently supported the prevailing view that younger children were at greater risk than senior ones. More times and longer duration of exposures to GA, and major surgeries may indicate a higher risk of negative outcomes.ConclusionBased on current studies, it is necessary to endeavor to limit the duration and numbers of anesthesia and the dose of anesthetic agents. For future studies, we require cohort studies with rich sources of data and appropriate outcome measures, and carefully designed and adequately powered clinical trials testing plausible interventions in relevant patient populations.

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Section: Resultsmentioning

confidence: 99%

General anesthesia in children and long-term neurodevelopmental deficits: A systematic review

Xiao

Yang

et al. 2022

Front. Mol. Neurosci.

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“…Two extant studies compared available magnetic resonance imaging structural imaging in children exposed and unexposed to anesthesia, 68,69 with another evaluating functional magnetic resonance imaging in nonhuman primates. 70 Although these studies have limitations, anesthetic exposure was found to be associated with imaging differences. Two ongoing National Institutes of Health–funded trials using prospectively collected magnetic resonance imaging images may provide further insight.…”

Section: What Evidence Would Be Required To Show That Exposure To General Anesthesia Causes Long-term Neurodevelopmental Deficits In Chilmentioning

confidence: 98%

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward

Ing

Warner²,

Sun

et al. 2022

Anesthesiology

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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.

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“…More recently, a study examined the brains of early-in-life anesthesia-exposed animals for structural changes in the white matter using magnetic resonance imaging (MRI) technology. 25 The reported findings, deriving from 2 primate cohorts at 2 separate centers with the animals' age either 12 or 18 months, showed that multiple short anesthesia exposures during early development were associated with alterations in white matter integrity. Animals in both cohorts had received 0 to 4 previous MRI sessions under short anesthesia with ketamine and/or isoflurane before undergoing diffusion MRI scans.…”

Section: Recent Neuroimaging Findingsmentioning

confidence: 99%

“…The results of these studies revealed that early-in-life exposure to volatile anesthetics increased glial activation, and the authors proposed this as a surrogate for neurotoxicity in the NHP brain. More recently, a study examined the brains of early-in-life anesthesia-exposed animals for structural changes in the white matter using magnetic resonance imaging (MRI) technology 25. The reported findings, deriving from 2 primate cohorts at 2 separate centers with the animals’ age either 12 or 18 months, showed that multiple short anesthesia exposures during early development were associated with alterations in white matter integrity.…”

Section: Update On Nonhuman Primate Studies Of Aidnmentioning

confidence: 99%

An Update on Preclinical Research in Anesthetic-Induced Developmental Neurotoxicity in Nonhuman Primate and Rodent Models

Neudecker

Thomas

et al. 2022

Journal of Neurosurgical Anesthesiology

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T he 2022 Pediatric Anesthesia and NeuroDevelopment Assessment (PANDA) Meeting included an update on preclinical research in the field of anestheticinduced developmental neurotoxicity (AIDN), with a focus on key developments since last meeting 3 years prior. The focus was on two areas: (1) The rapid growth in reports from nonhuman primate (NHP) studies, which play a pivotal role in understanding what elements of AIDN are likely to translate to human patients; and (2) The exploration of new targets, phenotypes, and exposure paradigms that have been conducted in rodent models. The purpose of this commentary article is to summarize this discussion and expand upon it both to update the reader on key developments in AIDN research and to highlight the importance of continued animal model research. UPDATE ON NONHUMAN PRIMATE STUDIES OF AIDNThe nonhuman primate (NHP) model is of value to the field of AIDN as clinical approaches are limited due to the ethical considerations of pediatric studies. The NHP is phylogenetically close to the human condition, sharing similarities in the development and complexity of their brain, in their cognitive functions, and in behavioral repertoire. Both species show similarities in social cohabitation, and social signals in both species depend on visual cues. In contrast, small animals such as rodents strongly rely on olfactory signals. Studies exposing infant NHPs to anesthetics have greatly contributed to the field of AIDN. 1 The most recent advances, including new knowledge about structural alterations and functional outcomes induced by early-in-life anesthesia exposure and the latest findings in neuroimaging studies and investigations of underlying mechanisms and mitigating strategies, are discussed. Newly Identified Structural AlterationsEarly histopathological studies in NHPs specified the complex gyrencephalic brain and expanded the understanding of acute neurotoxic effects on the immature brain caused by the exposure to diverse anesthetics that had been described from studies in rodent pups. [2][3][4][5][6][7] As little as 3 hours exposure to isoflurane on postnatal day 6

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General anaesthesia during infancy reduces white matter micro-organisation in developing rhesus monkeys

Cited by 18 publications

References 40 publications

General anesthesia in children and long-term neurodevelopmental deficits: A systematic review

General anesthesia in children and long-term neurodevelopmental deficits: A systematic review

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward

An Update on Preclinical Research in Anesthetic-Induced Developmental Neurotoxicity in Nonhuman Primate and Rodent Models

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