Early childhood general anaesthesia exposure and neurocognitive development
2010; Elsevier BV; Volume: 105; Linguagem: Inglês
10.1093/bja/aeq302
ISSN1471-6771
Autores Tópico(s)Intensive Care Unit Cognitive Disorders
ResumoSummaryA 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. 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. Key points•Preclinical evidence indicates anaesthetic exposure in neonatal animals leads to neurotoxicity and neurobehavioural deficits.•Available clinical studies related to anaesthetic neurotoxicity are retrospective and inconclusive.•Two multicentre clinical studies are currently underway to address anaesthetic neurotoxicity in children. •Preclinical evidence indicates anaesthetic exposure in neonatal animals leads to neurotoxicity and neurobehavioural deficits.•Available clinical studies related to anaesthetic neurotoxicity are retrospective and inconclusive.•Two multicentre clinical studies are currently underway to address anaesthetic neurotoxicity in children. An estimated 6 million children receive anaesthesia annually in the USA.1DeFrances CJ Cullen KA Kozak LJ National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data.Vital Health Stat. 2007; 13: 1-209Google Scholar Among infants, defined as those under 12 months of age, the Nationwide Inpatient Sample data indicate that 1.5 million undergo surgery as inpatients each year in the USA. Surgical anaesthesia provides amnesia, analgesia, immobility, and control of autonomic responses during surgical procedures. In the non-surgical setting, anaesthesia in children provides safe and appropriate conditions for interventional procedures, imaging studies, and diagnostic procedures. The benefits of anaesthesia in children include alleviation of pain, anxiety, maintaining stable vital signs, and providing adequate conditions for surgery or the procedures in question. These benefits have accounted for the exponential increase in the number of anaesthetics administered to children in many different settings, for many different procedures, and to children of increasingly younger age. The widespread and growing use of anaesthesia in infants and young children thus makes its safety a major public health issue of interest to the public, government agencies, and the anaesthesia community. This issue has become a matter of great concern with the evidence that anaesthetics are neurotoxic in animal studies. A conceptual framework for research related to the adverse health effects of anaesthesia exposure in vivo, in vitro, and in populo is presented in Figure 1. The goal of this review is to provide an overview of available clinical studies related to neurocognitive development and early childhood exposure to anaesthesia, including the outline of two large-scale ongoing clinical studies. The review only briefly summarizes the preclinical studies that have reported functional outcomes, which serve as important background information to the clinical studies. For a more comprehensive review of all of the preclinical studies on anaesthetic neurotoxicity, the reader is referred to other recent reviews.2Mellon RD Simone AF Rappaport BA Use of anesthetic agents in neonates and young children.Anesth Analg. 2007; 104: 509-520doi:10.1213/01.ane.0000255729.96438.b0Crossref PubMed Scopus (339) Google Scholar, 3Loepke AW Soriano SG An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function.Anesth Analg. 2008; 106: 1681-1707doi:10.1213/ane.0b013e318167ad77Crossref PubMed Scopus (389) Google Scholar, 4Istaphanous GK Loepke AW General anesthetics and the developing brain.Curr Opin Anaesthesiol. 2009; 22: 368-373doi:10.1097/ACO.0b013e3283294c9eCrossref PubMed Scopus (135) Google Scholar, 5Loepke AW Developmental neurotoxicity of sedatives and anesthetics: a concern for neonatal and pediatric critical care medicine?.Pediatr Crit Care Med. 2010; 11: 217-226Crossref PubMed Scopus (87) Google Scholar, 6Wilder RT Is there any relationship between long-term behavior disturbance and early exposure to anesthesia?.Curr Opin Anaesthesiol. 2010; 23: 332-336doi:10.1097/ACO.0b013e3283391f94Crossref PubMed Scopus (34) Google Scholar Experimental studies in animals (rats, mice, guinea pigs, piglets, and non-human primates) have shown that exposure of the developing mammalian brain to a variety of commonly used anaesthetic agents during critical developmental periods can lead to neuronal apoptosis or neurodegeneration in vitro and measureable neurobehavioural and functional deficits in vivo.2Mellon RD Simone AF Rappaport BA Use of anesthetic agents in neonates and young children.Anesth Analg. 2007; 104: 509-520doi:10.1213/01.ane.0000255729.96438.b0Crossref PubMed Scopus (339) Google Scholar, 3Loepke AW Soriano SG An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function.Anesth Analg. 2008; 106: 1681-1707doi:10.1213/ane.0b013e318167ad77Crossref PubMed Scopus (389) Google Scholar, 4Istaphanous GK Loepke AW General anesthetics and the developing brain.Curr Opin Anaesthesiol. 2009; 22: 368-373doi:10.1097/ACO.0b013e3283294c9eCrossref PubMed Scopus (135) Google Scholar 7Jevtovic-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; 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110: 813-825doi:10.1097/ALN.0b013e31819b602bCrossref PubMed Scopus (213) Google Scholar Ikonomidou and colleagues22Ikonomidou C Bosch F Miksa M et al.Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.Science. 1999; 283: 70-74doi:10.1126/science.283.5398.70Crossref PubMed Scopus (1703) Google Scholar first made the observation that N-methyl-d-aspartate glutamate receptor (NMDAR) antagonists induced extensive neuronal apoptosis in the developing rat brain. This has potentially important implications for clinical paediatric and obstetric anaesthesia since certain clinically used anaesthetic agents have similar mechanisms of action as NMDAR antagonists.22Ikonomidou C Bosch F Miksa M et al.Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain.Science. 1999; 283: 70-74doi:10.1126/science.283.5398.70Crossref PubMed Scopus (1703) Google Scholar The concern was thus raised with respect to the potential neurotoxic effects of other anaesthetic agents. Subsequently, studies by Jevtovic-Todorovic and colleagues7Jevtovic-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 and Fredriksson and colleagues20Fredriksson A Ponten E Gordh T Eriksson P Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits.Anesthesiology. 2007; 107: 427-436doi:10.1097/01.anes.0000278892.62305.9cCrossref PubMed Scopus (367) Google Scholar found the same pattern of in vitro neuronal apoptosis after exposure of the developing rat brain to anaesthetic agents that act as NMDAR antagonists and γ-aminobutyric acid type A receptor (GABAR) agonists. Jevtovic-Todorovic and colleagues7Jevtovic-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 exposed rats at postnatal day 7 to a ‘cocktail’ of clinically used anaesthetic agents (midazolam, isoflurane, and nitrous oxide) and demonstrated not only neuronal apoptosis in the infant rat brain, but also persistent functional deficits in memory and learning in juvenile rats, with impairment of both spatial reference and working memory in adult rats. Dose-dependent neuronal apoptosis in response to anaesthetics has been documented in both rodent and non-human primate studies. Ketamine induces neuronal apoptosis and neurodegeneration in both rats and monkeys with high doses, prolonged exposure, or repeated doses.2Mellon RD Simone AF Rappaport BA Use of anesthetic agents in neonates and young children.Anesth Analg. 2007; 104: 509-520doi:10.1213/01.ane.0000255729.96438.b0Crossref PubMed Scopus (339) Google Scholar 3Loepke AW Soriano SG An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function.Anesth Analg. 2008; 106: 1681-1707doi:10.1213/ane.0b013e318167ad77Crossref PubMed Scopus (389) Google Scholar 49Vutskits L Gascon E Kiss JZ Effects of ketamine on the developing central nervous system.Ideggyogy Sz. 2007; 60: 109-112PubMed Google Scholar 50Slikker Jr, W Zou X Hotchkiss CE et al.Ketamine-induced neuronal cell death in the perinatal rhesus monkey.Toxicol Sci. 2007; 98: 145-158doi:10.1093/toxsci/kfm084Crossref PubMed Scopus (490) Google Scholar 52Hayashi H Dikkes P Soriano SG Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain.Paediatr Anaesth. 2002; 12: 770-774doi:10.1046/j.1460-9592.2002.00883.xCrossref PubMed Scopus (164) Google Scholar Similar dose-dependent effects have been documented for propofol and isoflurane.3Loepke AW Soriano SG An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function.Anesth Analg. 2008; 106: 1681-1707doi:10.1213/ane.0b013e318167ad77Crossref PubMed Scopus (389) Google Scholar 20Fredriksson A Ponten E Gordh T Eriksson P Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits.Anesthesiology. 2007; 107: 427-436doi:10.1097/01.anes.0000278892.62305.9cCrossref PubMed Scopus (367) Google Scholar 37Yon JH Carter LB Reiter RJ Jevtovic-Todorovic V Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain.Neurobiol Dis. 2006; 21: 522-530doi:10.1016/j.nbd.2005.08.011Crossref PubMed Scopus (177) Google Scholar Neurotoxic effects were more prominent when the exposure was to a combination of anaesthetic agents with both NMDAR and GABAR actions than from exposure to an agent with either NMDAR or GABAR actions alone. Another important feature of anaesthetic neurotoxicity is that there is a critical period of vulnerability for exposure. Studies in rodents found neuronal apoptosis to be the greatest if exposure occurred at postnatal day 7, the period of peak synaptogenesis.10Stratmann 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: 834-848doi:10.1097/ALN.0b013e31819c463dCrossref PubMed Scopus (323) Google Scholar 50Slikker Jr, W Zou X Hotchkiss CE et al.Ketamine-induced neuronal cell death in the perinatal rhesus monkey.Toxicol Sci. 2007; 98: 145-158doi:10.1093/toxsci/kfm084Crossref PubMed Scopus (490) Google Scholar In non-human primates, exposure occurring at postnatal day 5, but not at postnatal day 35, was found to cause neurotoxicity. These preclinical studies indicate that neurotoxicity of anaesthetic agents in the developing brain, as evidenced by neuronal apoptosis and necrosis, is greatest if the exposure occurs during periods of peak synaptogenesis, with high doses or with a combination of anaesthetic agents. However, anaesthetic-induced neurotoxic effects involve more than neuronal apoptosis and necrosis during synaptogenesis. Several recent studies suggest that anaesthetics also inhibit neurogenesis and alter the development of dendritic spine architecture, important developmental processes in synapse formation 0.17Briner A De Roo M Dayer A Muller D Habre W Vutskits L Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis.Anesthesiology. 2010; 112: 546-556doi:10.1097/ALN.0b013e3181cd7942Crossref PubMed Scopus (193) Google Scholar 53Head BP Patel HH Niesman IR Drummond JC Roth DM Patel PM Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system.Anesthesiology. 2009; 110: 813-825doi:10.1097/ALN.0b013e31819b602bCrossref PubMed Scopus (213) Google Scholar Although much work remains to be done to elucidate the specific mechanisms of anaesthetic neurotoxicity, much progress has been made. One proposed mechanism is the inhibition of brain-derived neurotrophic factor (BDNF) signalling pathways by GABAergic and NMDAR-acting anaesthetic agents.25Lu LX Yon JH Carter LB Jevtovic-Todorovic V General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain.Apoptosis. 2006; 11: 1603-1615doi:10.1007/s10495-006-8762-3Crossref PubMed Scopus (207) Google Scholar 53Head BP Patel HH Niesman IR Drummond JC Roth DM Patel PM Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system.Anesthesiology. 2009; 110: 813-825doi:10.1097/ALN.0b013e31819b602bCrossref PubMed Scopus (213) Google Scholar BDNF has also been shown to be involved in the developmental neurotoxicity observed with lead exposure.54Neal AP Stansfield KH Worley PF Thompson RE Guilarte TR Lead exposure during synaptogenesis alters vesicular proteins and impairs vesicular release: potential role of NMDA receptor-dependent BDNF signaling.Toxicol Sci. 2010; 116: 249-263doi:10.1093/toxsci/kfq111Crossref PubMed Scopus (85) Google Scholar Most preclinical studies have examined the effects of various anaesthetics on histopathological changes in vitro. The focus of the present review is on those studies that also examined functional outcomes (Table 1).7Jevtovic-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 9Sanders RD Xu J Shu Y et al.Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats.Anesthesiology. 2009; 110: 1077-1085doi:10.1097/ALN.0b013e31819daeddCrossref PubMed Scopus (363) Google Scholar, 10Stratmann 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: 834-848doi:10.1097/ALN.0b013e31819c463dCrossref PubMed Scopus (323) Google Scholar, 11Stratmann G Sall JW May LD Loepke AW Lee MT Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long-term neurocognitive function.Anesth Analg. 2010; 110: 431-437Crossref Scopus (67) Google Scholar, 12Zhu 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: 1017-1030doi:10.1038/jcbfm.2009.274Crossref PubMed Scopus (241) Google Scholar, 13Rothstein S Simkins T Nunez JL Response to neonatal anesthesia: effect of sex on anatomical and behavioral outcome.Neuroscience. 2008; 152: 959-969doi:10.1016/j.neuroscience.2008.01.027Crossref PubMed Scopus (61) Google Scholar 20Fredriksson A Ponten E Gordh T Eriksson P Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits.Anesthesiology. 2007; 107: 427-436doi:10.1097/01.anes.0000278892.62305.9cCrossref PubMed Scopus (367) Google Scholar 24Loepke AW Istaphanous GK McAuliffe 3rd, JJ et al.The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory.Anesth Analg. 2009; 108: 90-104doi:10.1213/ane.0b013e31818cdb29Crossref PubMed Scopus (226) Google Scholar 45Bercker S Bert B Bittigau P et al.Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia.Neurotox Re
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