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W2122236648 abstract "It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental. Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age. Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis. Clinical data remain conflicting on the significance of these laboratory data to the paediatric population. At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery. The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer’s disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials. It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients. It has been assumed that anaesthetics have minimal or no persistent effects after emergence from anaesthesia. However, general anaesthetics act on multiple ion channels, receptors, and cell signalling systems in the central nervous system to produce anaesthesia, so it should come as no surprise that they also have non-anaesthetic actions that range from beneficial to detrimental. Accumulating evidence is forcing the anaesthesia community to question the safety of general anaesthesia at the extremes of age. Preclinical data suggest that inhaled anaesthetics can have profound and long-lasting effects during key neurodevelopmental periods in neonatal animals by increasing neuronal cell death (apoptosis) and reducing neurogenesis. Clinical data remain conflicting on the significance of these laboratory data to the paediatric population. At the opposite extreme in age, elderly patients are recognized to be at an increased risk of postoperative cognitive dysfunction (POCD) with a well-recognized decline in cognitive function after surgery. The underlying mechanisms and the contribution of anaesthesia in particular to POCD remain unclear. Laboratory models suggest anaesthetic interactions with neurodegenerative mechanisms, such as those linked to the onset and progression of Alzheimer’s disease, but their clinical relevance remains inconclusive. Prospective randomized clinical trials are underway to address the clinical significance of these findings, but there are major challenges in designing, executing, and interpreting such trials. It is unlikely that definitive clinical studies absolving general anaesthetics of neurotoxicity will become available in the near future, requiring clinicians to use careful judgement when using these profound neurodepressants in vulnerable patients. Editor’s key points•Alongside the desirable clinical effects, anaesthetic agents can be neurotoxic at the extremes of life.•As reviewed by Hudson and Hemmings, the preclinical data are strong but reconciling this with the clinical picture produces a complicated and often conflicting picture.•The authors underscore the need for robust prospective randomized clinical trials but highlight that these will be a challenge to the design; especially in standardizing the exposure and the measurement of outcome. •Alongside the desirable clinical effects, anaesthetic agents can be neurotoxic at the extremes of life.•As reviewed by Hudson and Hemmings, the preclinical data are strong but reconciling this with the clinical picture produces a complicated and often conflicting picture.•The authors underscore the need for robust prospective randomized clinical trials but highlight that these will be a challenge to the design; especially in standardizing the exposure and the measurement of outcome. General anaesthesia is a complex pharmacological response produced by a chemically heterogeneous class of drugs involving mechanisms that remain incompletely understood. Current concepts define anaesthesia by its core features of amnesia, unconsciousness, and immobility (in the order of decreasing potency), each mediated by pharmacological effects on specific neuronal networks in different regions of the central nervous system.1Rudolph U Antkowiak B Molecular and neuronal substrates for general anaesthetics.Nat Rev Neurosci. 2004; 5: 709-720Crossref PubMed Scopus (612) Google Scholar The molecular targets of these region- and dose-specific actions on neuronal network function have not been defined for most anaesthetics, although likely candidates have been identified and characterized. These include ligand-gated ion channels involved in inhibitory [receptors for γ-aminobutyric acid (GABA) and glycine] or excitatory [N-methyl-d-aspartate (NMDA) and AMPA subtype receptors for glutamate] synaptic transmission, ion channels conducting Na+, Ca2+, and K+ that regulate neuronal excitability and chemical transmission, and pleiotropic intracellular signalling pathways.2Hemmings Jr., HC Akabas MH Goldstein PA Trudell JR Orser BA Harrison NL Emerging molecular mechanisms of general anesthetic action.Trends Pharmacol Sci. 2005; 26: 503-510Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar This diversity of potential targets increases the probability of both positive and negative non-anaesthetic effects (Table 1).Table 1Putative anaesthetic, neurotoxic, and neuroprotective targets of general anaestheticsTargetAnaesthesiaNeurotoxicityNeuroprotectionSynaptic transmission GABAA receptors+++ NMDA receptors+++ Neuronal nicotinic acetylcholine receptors++Excitability Na+ channels+++ Ca2+ channels+++ K+ channels+++Intracellular signalling Protein kinase pathways?+ Alzheimer precursor protein (APP) processing++ Tau phosphorylation++ Open table in a new tab While the actions of the i.v. anaesthetics can often be ascribed primarily to one or a few targets, the potent inhaled anaesthetics (ethers and alkanes) appear to be particularly promiscuous, interacting with many functionally important targets, both in the nervous system and in other organs. As an example of the former, the anaesthetic effects of propofol and etomidate are mediated primarily though the potentiation of GABAA receptors as demonstrated in the resistance to immobility of a knock-in mouse harbouring a mutant receptor engineered to be insensitive to these drugs.3Jurd R Arras M Lambert S et al.General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.FASEB J. 2003; 17: 250-252Crossref PubMed Scopus (507) Google Scholar Analogous experiments have not been as conclusive for the inhaled anaesthetics, which are more than 100-fold less potent than i.v. anaesthetics and consequently are less selective in their target interactions. Nevertheless, i.v. and inhaled anaesthetics share overlapping effects on many targets including GABAA and NMDA receptors. Actions on these two targets implicated in the desirable effects of anaesthetics, and other effects on unrelated targets, have come under renewed scrutiny for their potential roles in mediating potentially long-lasting detrimental effects on the developing and mature brain. A defining feature of general anaesthetics is their ability to reversibly induce a coma-like state, but recent findings of changes in gene and protein expression persisting beyond emergence from anaesthesia provide a molecular basis for more durable effects.4Fütterer CD Maurer MH Schmitt A Feldmann Jr, RE Kuschinsky W Waschke KF Alterations in rat brain proteins after desflurane anesthesia.Anesthesiology. 2004; 100: 302-308Crossref PubMed Scopus (91) Google Scholar 5Culley DJ Yukhananov RY Xie Z Gali RR Tanzi RE Crosby G Altered hippocampal gene expression 2 days after general anesthesia in rats.Eur J Pharmacol. 2006; 549: 71-78Crossref PubMed Scopus (48) Google Scholar This brief review highlights some of the critical laboratory findings that have called attention to the neurotoxic effects of anaesthetics, and efforts to establish the clinical significance of potential effects of anaesthetics on neurodevelopmental outcome. The developing brain has several significant differences from the adult brain that provide a physiological basis for enhanced vulnerability to anaesthetics. Early in development the number of neurones formed is significantly greater than in adult mammals. At the same time, there is an exuberant burst of synapse formation (synaptogenesis) before synapses are eventually pruned to establish behaviourally relevant connections between neurones. Programmed cell death, or apoptosis, is responsible for the elimination of 50–70% of developing neurones under normal circumstances.6Oppenheim RW Cell death during development of the nervous system.Annu Rev Neurosci. 1991; 14: 453-501Crossref PubMed Scopus (2757) Google Scholar 7Rakic S Zecevic N Programmed cell death in the developing human telencephalon.Eur J Neurosci. 2000; 12: 2721-2734Crossref PubMed Scopus (167) Google Scholar Apoptosis is a highly regulated mechanism of controlled cell involution and death that has both physiological and pathological roles. This apoptotic pruning of brain cells establishes normal cortical architecture and function. Apoptosis also serves to remove neurones after pathological insults, such as ischaemia or hypoxia, after withdrawal of neurotrophic factors, and after exposure to anaesthesia in early development.8Yon JH Daniel-Johnson J Carter LB Jevtovic-Todorovic V Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways.Neuroscience. 2005; 135: 815-827Crossref PubMed Scopus (55) Google Scholar However, it is difficult to determine the extent to which apoptosis after anaesthesia involves cells that were already destined to die, or whether anaesthesia induces excessive apoptosis in viable cells that might negatively impact maturation of the nervous system. One significant difference between immature and mature mammalian brain with neuropharmacological implications is the developmentally regulated reversal of the transmembrane chloride gradient. This is relevant to anaesthetic effects as many anaesthetic agents enhance the activity of GABAA and glycine receptors, both of which are coupled to intrinsic chloride-conducting ion pores to increase the permeability of the cell membrane to chloride ions. In adults, expression of the KCC2 K+/Cl− cotransporter produces an inward electrochemical chloride gradient that results in inward chloride flux after enhanced chloride permeability of the GABA-gated ion channel. This leads to hyperpolarization of the neurone and resulting suppression of neuronal activity. However, early in development before KCC2 expression the gradient for chloride is reversed such that the increase in chloride permeability associated with GABAA or glycine receptor activation leads to depolarization of the neurone, with resultant excitation. Hyperexcitation in human neonates evident by electroencephalography has been reported with sevoflurane,9Veyckemans F Excitation phenomena during sevoflurane anaesthesia in children.Curr Opin Anaesthesiol. 2001; 14: 339-343Crossref PubMed Scopus (60) Google Scholar 10Constant I Seeman R Murat I Sevoflurane and epileptiform EEG changes.Paediatr Anaesth. 2005; 15: 266-274Crossref PubMed Scopus (183) Google Scholar isoflurane,11Harrison JL Postoperative seizures after isoflurane anesthesia.Anesth Anal. 1986; 65: 1235-1236Crossref PubMed Scopus (30) Google Scholar and propofol12Zeiler SR Kaplan PW Propofol withdrawal seizures (or not).Seizure. 2008; 17: 665-667Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar anaesthesia, and might be related to the developmental switch from N+–K+–2Cl2 cotransporter 1 (NKCC1) to KCC2 expression and the associated reversal of the chloride electrochemical potential that occurs perinatally in humans.13Dzhala VI Talos DM Sdrulla DA et al.NKCC1 transporter facilitates seizures in the developing brain.Nat Med. 2005; 11: 1205-1213Crossref PubMed Scopus (776) Google Scholar At least in immature rodents, exposure to either NMDA-type glutamate receptor antagonists or positive modulators of GABAA receptors can lead to increased apoptosis. Blockade of NMDA receptors by ketamine in the developing rodent brain causes excessive apoptosis.14Ikonomidou C Bosch F Miksa M et al.Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.Science. 1999; 283: 70-74Crossref PubMed Scopus (1718) Google Scholar 15Scallet AC Schmued LC Slikker Jr, W et al.Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons.Toxicol Sci. 2004; 81: 364-370Crossref PubMed Scopus (264) Google Scholar These early observations of ketamine neurotoxicity were of concern but were considered agent-specific. Evidence that more commonly used anaesthetics also produced neurodegeneration in neonatal animals elevated concerns. One particularly compelling study designed to model paediatric anaesthesia exposed rat pups on postnatal day P7 to a cocktail of isoflurane, midazolam, and nitrous oxide at levels sufficient to maintain a surgical plane of anaesthesia for 6 h.16Jevtovic-Todorovic V Hartman RE Izumi Y et al.Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits.J Neurosci. 2003; 23: 876-882Crossref PubMed Google Scholar Immediately after exposure, the rat pups developed excessive neuronal apoptosis throughout the brain, including the hippocampus and cerebral cortex. This apoptotic effect was significant both physiologically, with impairment of hippocampal long-term potentiation (an in vitro model of synaptic plasticity relevant to learning and memory), and behaviourally, with impairment of spatial reference memory as juveniles that persisted into adulthood. Isoflurane exposure alone led to significant apoptosis, but the addition of other agents to the cocktail substantially increased the degree of apoptosis. The increased neuronal death with additional agents suggests that the significant event might be the pharmacologically induced coma itself rather than the particular agent used to achieve the anaesthetic state. Indeed, equipotent exposure of neonatal mice to desflurane, isoflurane, and sevoflurane produced similar increases in apoptotic cell death.17Istaphanous GK Howard J Nan X et al.Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice.Anesthesiology. 2011; 114: 578-587Crossref PubMed Scopus (240) Google Scholar In addition to the data for ketamine and volatile anaesthetics, in vivo or in vitro data suggest increased neuronal cell death after neonatal animal exposure to midazolam,18Young C Jevtovic-Todorovic V Qin YQ et al.Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain.Br J Pharmacol. 2005; 146: 189-197Crossref PubMed Scopus (390) Google Scholar diazepam,19Ikonomidou C Bittigau P Ishimaru MJ et al.Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome.Science. 2000; 287: 1056-1060Crossref PubMed Scopus (1207) Google Scholar 20Bittigau P Sifringer M Genz K et al.Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.Proc Natl Acad Sci USA. 2002; 99: 15089-15094Crossref PubMed Scopus (642) Google Scholar clonazepam,19Ikonomidou C Bittigau P Ishimaru MJ et al.Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome.Science. 2000; 287: 1056-1060Crossref PubMed Scopus (1207) Google Scholar 20Bittigau P Sifringer M Genz K et al.Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.Proc Natl Acad Sci USA. 2002; 99: 15089-15094Crossref PubMed Scopus (642) Google Scholar propofol,21Cattano D Young C Straiko MM Olney JW Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain.Anesth Analg. 2008; 106: 1712-1714Crossref PubMed Scopus (220) Google Scholar 22Kahraman S Zup SL McCarthy MM Fiskum G GABAergic mechanism of propofol toxicity in immature neurons.J Neurosurg Anesthesiol. 2008; 20: 233-240Crossref PubMed Scopus (91) Google Scholar pentobarbital,20Bittigau P Sifringer M Genz K et al.Antiepileptic drugs and apoptotic neurodegeneration in the developing brain.Proc Natl Acad Sci USA. 2002; 99: 15089-15094Crossref PubMed Scopus (642) Google Scholar nitrous oxide,23Ma D Williamson P Januszewski A et al.Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain.Anesthesiology. 2007; 106: 746-753Crossref PubMed Scopus (240) Google Scholar and xenon.24Cattano D Williamson P Fukui K et al.Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain.Can J Anaesth. 2008; 55: 429-436Crossref PubMed Scopus (85) Google Scholar However, conflicting reports also exist showing no adverse effects after exposure to midazolam, ketamine, thiopental, propofol, nitrous oxide, isoflurane, sevoflurane, and xenon. Indeed, under some circumstances, xenon appears to rescue neurones from isoflurane-induced apoptosis.23Ma D Williamson P Januszewski A et al.Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain.Anesthesiology. 2007; 106: 746-753Crossref PubMed Scopus (240) Google Scholar Although concerns that derangements of physiological homeostasis secondary to anaesthesia might contribute to neurodegeneration are valid, a number of well-controlled studies have implicated the anaesthetic exposure itself as the cause. Collectively, these studies illustrate the significance of experimental details such as dosage, duration, timing, species, and outcome studied. Given evidence for developmental neurodegeneration in response to exposure to all major classes of anaesthetics, further studies are essential to determine the relative toxicity of specific agents and the possibility of concomitant administration of neuroprotective drugs to counteract the pro-apoptotic effects of anaesthetics. Since, at least under some conditions, essentially every anaesthetic agent has the potential to induce apoptosis in neonatal neurones, it is important to consider whether the anaesthetic state itself promotes apoptosis in the neonatal period. It has been proposed that anaesthetic suppression of spontaneous neuronal activity might lead to insufficient neurotrophic factor secretion in the developing nervous system.25Olney JW Young C Wozniak DF Ikonomidou C Jevtovic-Todorovic V Anesthesia-induced developmental neuroapoptosis. Does it happen in humans?.Anesthesiology. 2004; 101: 273-275Crossref PubMed Scopus (141) Google Scholar If anaesthetic-induced suppression of electrophysiological activity occurs during critical developmental periods, neurones that are pharmacologically ‘disconnected’ from the network might be pruned through apoptotic mechanisms. However, at ages relevant to anaesthetic neurodegeneration (P4–8 rats), a significant number of rats have evidence of epileptic seizures with sevoflurane anaesthesia, and both seizure activity and apoptosis could be mitigated by co-administration of bumetanide, an NKCC1 inhibitor. These findings, suggest that apoptosis after anaesthesia could be secondary to excitotoxicity rather than to the withdrawal of trophic factors.26Edwards DA Shah HP Cao W Gravenstein N Seubert CN Martynyuk AE Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain.Anesthesiology. 2010; 112: 567-575Crossref PubMed Scopus (120) Google Scholar It remains to be seen whether perturbation of the neonatal chloride gradient can rescue neurones from apoptosis under other conditions, but the idea that pharmacological prophylaxis for long-term cognitive deficits after neonatal anaesthesia might be possible is provocative (Table 1). Neurogenesis, or the creation of neurones, depends upon coordinated neuronal progenitor stem cell proliferation, neuronal differentiation, migration, and ultimately integration into active networks to ensure neuronal survival and appropriate function. Because increased neurogenesis could theoretically compensate for neuronal loss during the perinatal period, it has been hypothesized that persistent effects of perinatal anaesthetic exposure implies that perinatal exposure to anaesthesia also suppresses neurogenesis. Consistent with this hypothesis, rats exposed to isoflurane on P7 showed decreased neuronal progenitor proliferation with delayed-onset deficits in fear conditioning and spatial reference tasks.27Stratmann G Sall JW May LD et al.Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats.Anesthesiology. 2009; 110: 834-848Crossref PubMed Scopus (324) Google Scholar In a separate study, P14 rats exposed to isoflurane for 35 min daily for 4 days showed a decrease in hippocampal neuronal progenitor cells, decreased neurogenesis, and impaired object recognition and reversal learning compared with controls. Intriguingly, P60 rats (adults) exposed to isoflurane showed no cell death after exposure and had increased neuronal differentiation with an associated improvement in neurocognitive function on testing 8 weeks later, again highlighting the often contradictory effects of exposure to anaesthesia during different developmental windows.28Zhu C Gao J Karlsson N et al.Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents.J Cereb Blood Flow Metab. 2010; 30: 1017-1030Crossref PubMed Scopus (241) Google Scholar The clinical significance of these observations remains controversial. The most robust neurotoxicity data available in primates were obtained by exposure of rhesus monkey fetuses and newborns to 24 h of ketamine anaesthesia. This produced neurodegeneration assessed using biomarkers for apoptosis both at day 122 of gestation and at P5, but not at P35, while a smaller exposure of 3 h on P5 demonstrated no neurodegeneration.29Slikker Jr., W Zou X Hotchkiss CE et al.Ketamine-induced neuronal cell death in the perinatal rhesus monkey.Toxicol Sci. 2007; 98: 145-158Crossref PubMed Scopus (493) Google Scholar A shortcoming of this study, specifically that demonstration of biomarkers for apoptosis does not equate to a behaviourally significant lesion, was addressed by a follow-up work from the same group,30Paule MG Li M Allen RR et al.Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys.Neurotoxicol Teratol. 2011; 33: 220-230Crossref PubMed Scopus (441) Google Scholar which documented long-lasting cognitive deficits in rhesus monkeys after exposure to 24 h of ketamine anaesthesia at P5–6. The animals were longitudinally assessed with the Operant Test Battery from the National Center for Toxicological Research, a test battery for which monkey and human child performance is similar.31Paule MG Cranmer JM Wilkins JD Stern HP Hoffman EL Quantitation of complex brain function in children: preliminary evaluation using a nonhuman primate behavioral test battery.Neurotoxicology. 1988; 9: 367-378PubMed Google Scholar Beginning at 10 months of age, control animals outperformed ketamine-exposed animals in accuracy and response speed for a learning task and a colour and position discrimination task; this effect persisted for at least 10 months. While the study by Paule and colleagues is very suggestive, it did not attempt to define a dose–response curve for anaesthetic exposure effect on cognitive performance and it made no attempt to define the temporal boundaries of the critical developmental period for exposure. Nonetheless, a primate model has now demonstrated that a single, albeit prolonged, exposure to an anaesthetic during a critical neurodevelopmental period can have profound and long-lasting effects on cognitive performance. Demonstration of anaesthetic toxicity in animal models requires substantial exposure, both in dosage and duration. Some estimate of the minimum required exposure for a significant effect on neurodevelopment comes from studies that have demonstrated significant apoptotic and necrotic cell death in neonatal monkeys exposed to ketamine for 9 h29Slikker Jr., W Zou X Hotchkiss CE et al.Ketamine-induced neuronal cell death in the perinatal rhesus monkey.Toxicol Sci. 2007; 98: 145-158Crossref PubMed Scopus (493) Google Scholar or isoflurane for 5 h.32Brambrink AM Evers AS Avidan MS et al.Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain.Anesthesiology. 2010; 112: 834-841Crossref PubMed Scopus (450) Google Scholar Ketamine exposure for 3 h was not sufficient to induce massive cell death,33Zou X Patterson TA Divine RL et al.Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain.Int J Dev Neurosci. 2009; 27: 727-731Crossref PubMed Scopus (198) Google Scholar so it is possible that there is an exposure threshold, or minimum dose time exposure time, for neurodegeneration. Information regarding the minimal neurotoxic dose and duration in humans would be extremely useful in defining the margin of neurological safety for specific anaesthetics. But it will be impossible to reliably obtain such data until specific non-invasive biomarkers for apoptotic neurodegeneration are developed. Anaesthetic exposure must occur during the critical period of neurogenesis and synaptogenesis to have significant apoptotic sequelae. It is difficult to compare data from rodents, which are altricial species that have a late postnatal brain growth spurt, to primates, which are precocial species with exuberant in utero brain growth spurts. Further complicating the translation of animal studies to humans are species differences in developmental timelines. The rat critical period for anaesthesia exposure resulting in neurotoxicity [(P0–P14) approximates the 20th week of gestation in humans], while the rhesus monkey critical period for anaesthetic neurodegeneration approximates the 26th week of gestation in humans.34Clancy B Finlay BL Darlington RB Anand KJ Extrapolating brain development from experimental species to humans.Neurotoxicology. 2007; 28: 931-937Crossref PubMed Scopus (645) Google Scholar Thus, anaesthetic neurotoxicity is probably most significant for the premature human fetus rather than term neonates or infants. However, there is a paucity of human data to support or refute the clinical extrapolation of these animal data. While it is likely that early exposure to anaesthesia can, under certain circumstances, lead to long-term cognitive deficits in humans, the only data that can be directly levelled at the problem at this time is necessarily retrospective. In one case series, children exposed to multiple anaesthetics before the age of 4 yr had twice the incidence of learning disability diagnoses later in life compared with age-matched birth cohort controls.35Wilder RT Flick RP Sprung J et al.Early exposure to anesthesia and learning disabilities in a population-based birth cohort.Anesthesiology. 2009; 110: 796-804Crossref PubMed Scopus (1103) Google Scholar Another retrospective cohort study examining enrollees of the New York State Medicaid system found that children who underwent hernia repair before 3 yr of age were more than twice as likely than age-matched controls to have a developmental or behavioural disorder diagnosis.36DiMaggio C Sun LS Kakavouli A Byrne MW Li G A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children.J Neurosurg Anesthesiol. 2009; 21: 286-291Crossref PubMed Scopus (417) Google Scholar Of course, these data cannot distinguish the relative roles of surgery, anaesthesia, or comorbid conditions, and hence remain suggestive but inconclusive. A twin study conducted by Bartels and colleagues that attempted to eliminate genetic confounders by comparing learning disabilities in identical twins concordant or not for early anaesthetic exposure did not support a role for anaesthesia in the development of subsequent learning disabilities.37Bartels M Althoff RR Boomsma DI Anesthesia and cognitive performance in children: no evidence for a causal relationship.Twin Res Hum Genet. 2009; 12: 246-253Crossref PubMed Scopus (308) Google Scholar The long-term cognitive effects of early anaesthetic exposure consequently remain an area of active enquiry, supported by the US Food and Drug Administration in collaboration with the International Anesthesia Research Society through the SmartTots programme (www.smarttots.org). Prospective randomized studies are clearly required to help clarify these issues of long-term cognitive effects of early anaesthetic exposure in humans given the limitations inherent in retrospective studies. But the design and execution of prospective studies is non-trivial and y" @default.
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W2122236648 title "Are anaesthetics toxic to the brain?" @default.
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