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Published in: Current Neurology and Neuroscience Reports 2/2011

01-04-2011

Newly Postulated Neurodevelopmental Risks of Pediatric Anesthesia

Authors: Stephen R. Hays, Jayant K. Deshpande

Published in: Current Neurology and Neuroscience Reports | Issue 2/2011

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Abstract

Recent animal and human studies have raised concern that exposure to anesthetic agents in children may cause neuronal damage and be associated with adverse neurodevelopmental outcomes. Exposure of young animals to anesthetic agents above threshold doses and durations during a critical neurodevelopmental window in the absence of concomitant painful stimuli causes widespread neuronal apoptosis and subsequent abnormal behaviors. The relevance of such animal data to humans is unknown. Untreated neonatal pain and stress also are associated with enhanced neuronal death and subsequent maladaptive behaviors, which can be prevented by exposure to these same anesthetic agents. Retrospective observational human studies have suggested a dose-dependent association between multiple anesthetic exposures in early childhood and subsequent learning disability, the causality of which is unknown. Ongoing prospective investigations are underway, the results of which may clarify if and what neurodevelopmental risks are associated with pediatric anesthesia. No change in current practice is yet indicated.
Literature
1.
go back to reference Eckenhoff JE: Relationship of anesthesia to postoperative personality changes in children. AMA Am J Dis Child 1953, 86:587–591.PubMed Eckenhoff JE: Relationship of anesthesia to postoperative personality changes in children. AMA Am J Dis Child 1953, 86:587–591.PubMed
2.
go back to reference Ikonomidou C, Bosch F, Miksa M, et al.: Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999, 283:70–74.PubMedCrossRef Ikonomidou C, Bosch F, Miksa M, et al.: Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999, 283:70–74.PubMedCrossRef
3.
go back to reference Ikonomidou C, Bittigau P, Ishimaru MJ, et al.: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000, 287:1056–1060.PubMedCrossRef Ikonomidou C, Bittigau P, Ishimaru MJ, et al.: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000, 287:1056–1060.PubMedCrossRef
4.
go back to reference Anand KJ, Aranda JV, Berde CB, et al.: Summary proceedings from the neonatal pain-control group. Pediatrics 2006, 117(3 Pt 2):S9–S22.PubMed Anand KJ, Aranda JV, Berde CB, et al.: Summary proceedings from the neonatal pain-control group. Pediatrics 2006, 117(3 Pt 2):S9–S22.PubMed
5.
go back to reference Anand KJ, Scalzo FM: Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate 2000, 77:69–82.PubMedCrossRef Anand KJ, Scalzo FM: Can adverse neonatal experiences alter brain development and subsequent behavior? Biol Neonate 2000, 77:69–82.PubMedCrossRef
7.
go back to reference Anand KJ, Garg S, Rovnaghi CR, et al.: Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res 2007 62:283–290.PubMedCrossRef Anand KJ, Garg S, Rovnaghi CR, et al.: Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res 2007 62:283–290.PubMedCrossRef
8.
go back to reference •• Rovnaghi CR, Garg S, Hall RW, et al.: Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects. Behav Brain Funct 2008, 4:35. Exposure to ketamine reduces both abnormal neuropathology and subsequent maladaptive behaviors in an animal model of neonatal pain; anesthesia to treat pain is neuroprotective, not neurotoxic.PubMedCrossRef •• Rovnaghi CR, Garg S, Hall RW, et al.: Ketamine analgesia for inflammatory pain in neonatal rats: a factorial randomized trial examining long-term effects. Behav Brain Funct 2008, 4:35. Exposure to ketamine reduces both abnormal neuropathology and subsequent maladaptive behaviors in an animal model of neonatal pain; anesthesia to treat pain is neuroprotective, not neurotoxic.PubMedCrossRef
9.
go back to reference Olney JW, Young C, Wozniak DF, et al.: Anesthesia-induced developmental neuroapoptosis: does it happen in humans? Anesthesiology 2004, 101:273–275.PubMedCrossRef Olney JW, Young C, Wozniak DF, et al.: Anesthesia-induced developmental neuroapoptosis: does it happen in humans? Anesthesiology 2004, 101:273–275.PubMedCrossRef
10.
go back to reference Wang C, Sadovova N, Hotchkiss C, et al.: Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture. Toxicol Sci 2006, 91:192–201.PubMedCrossRef Wang C, Sadovova N, Hotchkiss C, et al.: Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture. Toxicol Sci 2006, 91:192–201.PubMedCrossRef
11.
go back to reference Mellon RD, Simone AF, Rappaport BA: Use of anesthetic agents in neonates and young children. Anesth Analg 2007, 104:509–520.PubMedCrossRef Mellon RD, Simone AF, Rappaport BA: Use of anesthetic agents in neonates and young children. Anesth Analg 2007, 104:509–520.PubMedCrossRef
12.
go back to reference Slikker W Jr, Zou X, Hotchkiss CE, et al.: Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007, 98:145–158.PubMedCrossRef Slikker W Jr, Zou X, Hotchkiss CE, et al.: Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 2007, 98:145–158.PubMedCrossRef
13.
go back to reference •• Zou X, Patterson TA, Sadovova N, et al.: Potential neurotoxicity of ketamine in the developing rat brain. Toxicol Sci 2009, 108:149–158. Anesthetic neurotoxicity demonstrates both a threshold effect and a dose-response relationship: ketamine exposure below certain doses and durations was not associated with increased neuronal apoptosis in perinatal rhesus monkeys.PubMedCrossRef •• Zou X, Patterson TA, Sadovova N, et al.: Potential neurotoxicity of ketamine in the developing rat brain. Toxicol Sci 2009, 108:149–158. Anesthetic neurotoxicity demonstrates both a threshold effect and a dose-response relationship: ketamine exposure below certain doses and durations was not associated with increased neuronal apoptosis in perinatal rhesus monkeys.PubMedCrossRef
14.
go back to reference Bhutta AT, Venkatesan AK, Rovnaghi CR, et al.: Anaesthetic neurotoxicity in rodents: is the ketamine controversy real? Acta Paediatr 2007, 96:1554–1556.PubMedCrossRef Bhutta AT, Venkatesan AK, Rovnaghi CR, et al.: Anaesthetic neurotoxicity in rodents: is the ketamine controversy real? Acta Paediatr 2007, 96:1554–1556.PubMedCrossRef
15.
go back to reference Satomoto M, Satoh Y, Terui K, et al.: Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 2009, 110:628–637.PubMedCrossRef Satomoto M, Satoh Y, Terui K, et al.: Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 2009, 110:628–637.PubMedCrossRef
16.
go back to reference Joint letter to the Anesthetic and Life Support Drugs Committee of the U.S. Food and Drug Administration from the American Society of Anesthesiologists, the Society for Pediatric Anesthesia, and the American Academy of Pediatrics, March 15, 2007. Joint letter to the Anesthetic and Life Support Drugs Committee of the U.S. Food and Drug Administration from the American Society of Anesthesiologists, the Society for Pediatric Anesthesia, and the American Academy of Pediatrics, March 15, 2007.
17.
go back to reference •• Kalkman CJ, Peelen L, Moons KG, et al.: Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology 2009, 110:805–812. Retrospective observational study indicating urologic surgery under general anesthesia in children under 6 years of age is not associated with abnormal neurobehavioral scores, regardless of age at time of surgery.PubMedCrossRef •• Kalkman CJ, Peelen L, Moons KG, et al.: Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology 2009, 110:805–812. Retrospective observational study indicating urologic surgery under general anesthesia in children under 6 years of age is not associated with abnormal neurobehavioral scores, regardless of age at time of surgery.PubMedCrossRef
18.
go back to reference •• Wilder RT, Flick RP, Sprung J, et al.: Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009, 110:796–804. Retrospective observational study indicating children with histories of multiple, but not single, exposures to general anesthesia before 4 years of age had higher subsequent risk for learning disability; impossible to assess whether anesthetic exposure was causal to this association, or merely a marker for other underlying risk factor(s).PubMedCrossRef •• Wilder RT, Flick RP, Sprung J, et al.: Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009, 110:796–804. Retrospective observational study indicating children with histories of multiple, but not single, exposures to general anesthesia before 4 years of age had higher subsequent risk for learning disability; impossible to assess whether anesthetic exposure was causal to this association, or merely a marker for other underlying risk factor(s).PubMedCrossRef
19.
go back to reference • Bartels M, Althoff RR, Boomsma DI: Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet 2009, 12:246–253. Retrospective observational study demonstrating increased risk of learning disability in children exposed to anesthesia before 3 years of age, but not in twin pairs discordant for such exposure; the assertion that these data exonerate anesthesia as a causative factor in this association has been controversial.PubMedCrossRef • Bartels M, Althoff RR, Boomsma DI: Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet 2009, 12:246–253. Retrospective observational study demonstrating increased risk of learning disability in children exposed to anesthesia before 3 years of age, but not in twin pairs discordant for such exposure; the assertion that these data exonerate anesthesia as a causative factor in this association has been controversial.PubMedCrossRef
20.
go back to reference Loepke AW, Soriano SG: An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg 2008, 106:1681–1707.PubMedCrossRef Loepke AW, Soriano SG: An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg 2008, 106:1681–1707.PubMedCrossRef
21.
go back to reference Istaphanous GK, Loepke AW: General anesthetics and the developing brain. Curr Opin Anaesthesiol 2009, 22:368–373.PubMedCrossRef Istaphanous GK, Loepke AW: General anesthetics and the developing brain. Curr Opin Anaesthesiol 2009, 22:368–373.PubMedCrossRef
22.
go back to reference Wilder RT: Is there any relationship between long-term behavior disturbance and early exposure to anesthesia? Curr Opin Anaesthesiol. 2010, 23:332–336.PubMedCrossRef Wilder RT: Is there any relationship between long-term behavior disturbance and early exposure to anesthesia? Curr Opin Anaesthesiol. 2010, 23:332–336.PubMedCrossRef
23.
go back to reference Sanders RD, Ma D, Brooks P, et al.: Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity. Br J Anaesth 2008, 101:597–609.PubMedCrossRef Sanders RD, Ma D, Brooks P, et al.: Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity. Br J Anaesth 2008, 101:597–609.PubMedCrossRef
24.
go back to reference McGowan FX Jr, Davis PJ: Anesthetic-related neurotoxicity in the developing infant: of mice, rats, monkeys and, possibly, humans. Anesth Analg 2008, 106:1599–1602.PubMedCrossRef McGowan FX Jr, Davis PJ: Anesthetic-related neurotoxicity in the developing infant: of mice, rats, monkeys and, possibly, humans. Anesth Analg 2008, 106:1599–1602.PubMedCrossRef
25.
go back to reference McCann ME, Bellinger DC, Davidson AJ, et al.: Clinical research approaches to studying pediatric anesthetic neurotoxicity. Neurotoxicology. 2009, 30:766–771.PubMedCrossRef McCann ME, Bellinger DC, Davidson AJ, et al.: Clinical research approaches to studying pediatric anesthetic neurotoxicity. Neurotoxicology. 2009, 30:766–771.PubMedCrossRef
Metadata
Title
Newly Postulated Neurodevelopmental Risks of Pediatric Anesthesia
Authors
Stephen R. Hays
Jayant K. Deshpande
Publication date
01-04-2011
Publisher
Current Science Inc.
Published in
Current Neurology and Neuroscience Reports / Issue 2/2011
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-010-0177-4

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