Weiser, T. G. et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet 372, 139–144 (2008).
Eckenhoff, J. E. Relationship of anesthesia to postoperative personality changes in children. Am. J. Dis. Child. 86, 587–591 (1953).
Bedford, P. D. Adverse cerebral effects of anaesthesia on old people. Lancet 6, 259–263 (1955).
Servick, K. Researchers struggle to gauge risks of childhood anesthesia. Science 346, 1161–1162 (2014).
Rappaport, B. A., Suresh, S., Hertz, S., Evers, A. S. & Orser, B. A. Anesthetic neurotoxicity — clinical implications of animal models. N. Engl. J. Med. 372, 796–797 (2015).
Boney, O. et al. Identifying research priorities in anaesthesia and perioperative care: final report of the joint National Institute of Academic Anaesthesia/James Lind Alliance Research Priority Setting Partnership. BMJ Open 5, e010006 (2015).
Hensch, T. K. Critical period plasticity in local cortical circuits. Nat. Rev. Neurosci. 6, 877–888 (2005).
Burke, S. N. & Barnes, C. A. Neural plasticity in the ageing brain. Nat. Rev. Neurosci. 7, 30–40 (2006).
Jevtovic-Todorovic, V. et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J. Neurosci. 23, 876–882 (2003).
This paper is the first to demonstrate that exposure to anaesthesia in the early postnatal period can induce histological, functional and behavioural alterations in the developing brain.
Stratmann, G., Sall, J. W., May, L. D., Loepke, A. W. & Lee, M. T. Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long-term neurocognitive function. Anesth. Analg. 110, 431–437 (2010).
Loepke, A. W. & Soriano, S. G. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth. Analg. 106, 1681–1707 (2008).
Lin, E. P., Soriano, S. G. & Loepke, A. W. Anesthetic neurotoxicity. Anesthesiol. Clin. 32, 133–155 (2014).
Paule, M. G. et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol. Teratol. 33, 220–230 (2011).
Raper, J., Alvarado, M. C., Murphy, K. L. & Baxter, M. G. Multiple anesthetic exposure in infant monkeys alters emotional reactivity to an acute stressor. Anesthesiology 123, 1084–1092 (2015).
This publication demonstrates that exposure of NHP infants to the commonly used anaesthetic agent sevoflurane can induce lasting alterations in emotional reactivity.
Raper, J., Bush, A., Murphy, K. L., Baxter, M. G. & Alvarado, M. C. Multiple sevoflurane exposures in infant monkeys do not impact the mother-infant bond. Neurotoxicol. Teratol. 54, 46–51 (2016).
Sanders, R. D. et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 110, 1077–1085 (2009).
Fredriksson, A., Archer, T., Alm, H., Gordh, T. & Eriksson, P. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav. Brain Res. 153, 367–376 (2004).
Fredriksson, A., Ponten, E., Gordh, T. & Eriksson, P. Neonatal exposure to a combination of N-methyl-d-aspartate and γ-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 107, 427–436 (2007).
Yu, D., Jiang, Y., Gao, J., Liu, B. & Chen, P. Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci. Lett. 534, 41–46 (2013).
Qiu, L. et al. Acute and long-term effects of brief sevoflurane anesthesia during the early postnatal period in rats. Toxicol. Sci. 149, 121–133 (2016).
Shen, X. et al. Early life exposure to sevoflurane impairs adulthood spatial memory in the rat. Neurotoxicology 39, 45–56 (2013).
Shen, X. et al. Selective anesthesia-induced neuroinflammation in developing mouse brain and cognitive impairment. Anesthesiology 118, 502–515 (2013).
Stratmann, G. et al. Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats. Anesthesiology 110, 834–848 (2009).
Ponten, E., Fredriksson, A., Gordh, T., Eriksson, P. & Viberg, H. Neonatal exposure to propofol affects BDNF but not CaMKII, GAP-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain. Behav. Brain Res. 223, 75–80 (2011).
Zhu, C. 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. 30, 1017–1030 (2010).
Lee, B. H., Chan, J. T., Kraeva, E., Peterson, K. & Sall, J. W. Isoflurane exposure in newborn rats induces long-term cognitive dysfunction in males but not females. Neuropharmacology 83, 9–17 (2014).
This publication convincingly shows that the neurocognitive effect of early-life anaesthesia exposure is sex dependent and that the extent of anaesthesia-induced neuroapoptosis does not determine cognitive function.
Ikonomidou, C. et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283, 70–74 (1999).
Ikonomidou, C. et al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287, 1056–1060 (2000).
This work can be considered as the one that provided the biological rational to evaluate the effect of anaesthesia on the developing brain.
Gentry, K. R., Steele, L. M., Sedensky, M. M. & Morgan, P. G. Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans. Anesth. Analg. 116, 185–189 (2013).
Brambrink, A. M. et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 112, 834–841 (2010).
Lu, L. X., Yon, J. H., Carter, L. B. & Jevtovic-Todorovic, V. General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 11, 1603–1615 (2006).
This publication provides valuable insights into the molecular mechanisms underlying anaesthesia-induced neuroapoptosis.
Brambrink, A. M. et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann. Neurol. 72, 525–535 (2012).
Istaphanous, G. K. et al. Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex. Anesth. Analg. 116, 845–854 (2013).
Creeley, C. et al. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br. J. Anaesth. 110 (Suppl. 1), i29–i38 (2013).
Young, C. et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br. J. Pharmacol. 146, 189–197 (2005).
Istaphanous, G. K. et al. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology 114, 578–587 (2011).
Osterop, S. F. et al. Developmental stage-dependent impact of midazolam on calbindin, calretinin and parvalbumin expression in the immature rat medial prefrontal cortex during the brain growth spurt. Int. J. Dev. Neurosci. 45, 19–28 (2015).
Ma, D., Wilhelm, S., Maze, M. & Franks, N. P. Neuroprotective and neurotoxic properties of the 'inert' gas, xenon. Br. J. Anaesth. 89, 739–746 (2002).
Massa, H., Lacoh, C. & Vutskits, L. Effects of morphine on the differentiation and survival of developing pyramidal neurons during the brain growth spurt. Toxicol. Sci. 130, 168–179 (2012).
Deng, W., Aimone, J. B. & Gage, F. H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 11, 339–350 (2010).
Tashiro, A., Sandler, V. M., Toni, N., Zhao, C. & Gage, F. H. NMDA-receptor-mediated, cell-specific integration of new neurons in adult dentate gyrus. Nature 442, 929–933 (2006).
Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).
Stratmann, G. et al. Isoflurane does not affect brain cell death, hippocampal neurogenesis, or long-term neurocognitive outcome in aged rats. Anesthesiology 112, 305–315 (2010).
Krzisch, M. et al. Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology 118, 602–610 (2013).
Hofacer, R. D. et al. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann. Neurol. 73, 695–704 (2013).
This paper and reference 44 demonstrate that the neuronal vulnerability to anaesthetics depends on the developmental stage of individual neurons.
De Felipe, J., Marco, P., Fairen, A. & Jones, E. G. Inhibitory synaptogenesis in mouse somatosensory cortex. Cereb. Cortex 7, 619–634 (1997).
Briner, A. et al. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 115, 282–293 (2011).
This work shows that the administration of GAs in the early postnatal period can induce lasting changes in the number of dendritic spines and synapses, and demonstrates that the direction of these changes depends on the developmental stage at drug exposure.
Head, B. P. et al. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology 110, 813–825 (2009).
This publication describes a molecular pathway linking anaesthesia exposure to synapse loss and cell death.
Lunardi, N., Ori, C., Erisir, A. & Jevtovic-Todorovic, V. General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats. Neurotox. Res. 17, 179–188 (2010).
Lunardi, N., Oklopcic, A., Prillaman, M., Erisir, A. & Jevtovic-Todorovic, V. Early exposure to general anesthesia disrupts spatial organization of presynaptic vesicles in nerve terminals of the developing rat subiculum. Mol. Neurobiol. 52, 942–951 (2015).
Amrock, L. G., Starner, M. L., Murphy, K. L. & Baxter, M. G. Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology 122, 87–95 (2015).
DiGruccio, M. R. et al. Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development. J. Neurosci. 35, 1481–1492 (2015).
Joksovic, P. M., Lunardi, N., Jevtovic-Todorovic, V. & Todorovic, S. M. Early exposure to general anesthesia with isoflurane downregulates inhibitory synaptic neurotransmission in the rat thalamus. Mol. Neurobiol. 52, 952–958 (2015).
Briner, A. et al. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology 112, 546–556 (2010).
De Roo, M. et al. Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS ONE 4, e7043 (2009).
This paper describes dendritic spine dynamics upon anaesthesia exposure.
Vutskits, L. General anesthesia: a gateway to modulate synapse formation and neural plasticity? Anesth. Analg. 115, 1174–1182 (2012).
Mintz, C. D., Barrett, K. M., Smith, S. C., Benson, D. L. & Harrison, N. L. Anesthetics interfere with axon guidance in developing mouse neocortical neurons in vitro via a γ-aminobutyric acid type A receptor mechanism. Anesthesiology 118, 825–833 (2013).
Rudolph, U. & Antkowiak, B. Molecular and neuronal substrates for general anaesthetics. Nat. Rev. Neurosci. 5, 709–720 (2004).
Yon, J. H., Daniel-Johnson, J., Carter, L. B. & Jevtovic-Todorovic, V. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 135, 815–827 (2005).
Popic, J. et al. Propofol-induced changes in neurotrophic signaling in the developing nervous system in vivo. PLoS ONE 7, e34396 (2012).
Lemkuil, B. P. et al. Isoflurane neurotoxicity is mediated by p75NTR-RhoA activation and actin depolymerization. Anesthesiology 114, 49–57 (2011).
Pearn, M. L. et al. Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiology 116, 352–361 (2012).
Sanchez, V. et al. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 115, 992–1002 (2011).
Boscolo, A. et al. Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain. Anesthesiology 118, 1086–1097 (2013).
This publication describes anaesthesia exposure-induced mitochondrial dysfunction as a plausible cause of anaesthesia neurotoxicity.
Boscolo, A. et al. The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: the importance of free oxygen radicals and mitochondrial integrity. Neurobiol. Dis. 45, 1031–1041 (2012).
Kargaran, P. et al. Impact of propofol anaesthesia on cytokine expression profiles in the developing rat brain: a randomised placebo-controlled experimental in-vivo study. Eur. J. Anaesthesiol. 32, 336–345 (2015).
Zhang, L. et al. The potential dual effects of sevoflurane on AKT/GSK3β signaling pathway. Med. Gas Res. 4, 5 (2014).
Takesian, A. E. & Hensch, T. K. Balancing plasticity/stability across brain development. Prog. Brain Res. 207, 3–34 (2013).
Tao, G. et al. Sevoflurane induces tau phosphorylation and glycogen synthase kinase 3β activation in young mice. Anesthesiology 121, 510–527 (2014).
Eckenhoff, R. G. & Laudansky, K. F. Anesthesia, surgery, illness and Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 47, 162–166 (2012).
Silverstein, J. H. Influence of anesthetics on Alzheimer's disease: biophysical, animal model, and clinical reports. J. Alzheimers Dis. 40, 839–848 (2014).
Inouye, S. K., Westendorp, R. G. & Saczynski, J. S. Delirium in elderly people. Lancet 383, 911–922 (2014).
Culley, D. J., Baxter, M., Yukhananov, R. & Crosby, G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth. Analg. 96, 1004–1009 (2003).
Culley, D. J., Baxter, M. G., Yukhananov, R. & Crosby, G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology 100, 309–314 (2004).
Callaway, J. K., Jones, N. C., Royse, A. G. & Royse, C. F. Sevoflurane anesthesia does not impair acquisition learning or memory in the Morris water maze in young adult and aged rats. Anesthesiology 117, 1091–1101 (2012).
Li, C., Liu, S., Xing, Y. & Tao, F. The role of hippocampal tau protein phosphorylation in isoflurane-induced cognitive dysfunction in transgenic APP695 mice. Anesth. Analg. 119, 413–419 (2014).
Le Freche, H. et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology 116, 779–787 (2012).
Callaway, J. K., Jones, N. C., Royse, A. G. & Royse, C. F. Memory impairment in rats after desflurane anesthesia is age and dose dependent. J. Alzheimers Dis. 44, 995–1005 (2015).
Lee, I. H. et al. Spatial memory is intact in aged rats after propofol anesthesia. Anesth. Analg. 107, 1211–1215 (2008).
Xie, G., Zhang, W., Chang, Y. & Chu, Q. Relationship between perioperative inflammatory response and postoperative cognitive dysfunction in the elderly. Med. Hypotheses 73, 402–403 (2009).
Baranov, D. et al. Consensus statement: first international workshop on anesthetics and Alzheimer's disease. Anesth. Analg. 108, 1627–1630 (2009).
Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).
Bianchi, S. L. et al. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiol. Aging 29, 1002–1010 (2008).
Perucho, J. et al. Anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer's disease. J. Alzheimers Dis. 19, 1245–1257 (2010).
Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).
Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287–13292 (1997).
Eckel, B. et al. Effects of isoflurane-induced anaesthesia on cognitive performance in a mouse model of Alzheimer's disease: a randomised trial in transgenic APP23 mice. Eur. J. Anaesthesiol. 30, 605–611 (2013).
Oddo, S. et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421 (2003).
Tang, J. X. & Eckenhoff, M. F. Anesthetic effects in Alzheimer transgenic mouse models. Prog. Neuropsychopharmacol. Biol. Psychiatry 47, 167–171 (2012).
Xie, Z. et al. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid β-protein level in vivo. Ann. Neurol. 64, 618–627 (2008).
This is the first publication to show that anaesthesia exposure in vivo can induce pathological features of AD in experimental animals.
Valentim, A. M. et al. Lower isoflurane concentration affects spatial learning and neurodegeneration in adult mice compared with higher concentrations. Anesthesiology 113, 1099–1108 (2010).
Lin, D. & Zuo, Z. Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats. Neuropharmacology 61, 1354–1359 (2011).
Eckenhoff, R. G. et al. Inhaled anesthetic enhancement of amyloid-β oligomerization and cytotoxicity. Anesthesiology 101, 703–709 (2004).
This in vitro work is the first to demonstrate that anaesthetics can increase pathological events that are associated with AD.
Xie, Z. et al. The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid β protein levels. Anesthesiology 104, 988–994 (2006).
Xie, Z. et al. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid β-protein accumulation. J. Neurosci. 27, 1247–1254 (2007).
Zhen, Y. et al. Nitrous oxide plus isoflurane induces apoptosis and increases β-amyloid protein levels. Anesthesiology 111, 741–752 (2009).
Dong, Y. et al. The common inhalational anesthetic sevoflurane induces apoptosis and increases β-amyloid protein levels. Arch. Neurol. 66, 620–631 (2009).
Tanzi, R. E. & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545–555 (2005).
Planel, E. et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J. Neurosci. 27, 3090–3097 (2007).
Planel, E. et al. Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo. J. Neurosci. 28, 12798–12807 (2008).
Planel, E. et al. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. FASEB J. 23, 2595–2604 (2009).
Whittington, R. A. et al. Propofol directly increases tau phosphorylation. PLoS ONE 6, e16648 (2011).
Whittington, R. A. et al. Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro. Neurobiol. Aging 36, 2414–2428 (2015).
Tang, J. X. et al. Anesthesia in presymptomatic Alzheimer's disease: a study using the triple-transgenic mouse model. Alzheimers Dement. 7, 521–531.e1 (2011).
Dong, Y., Wu, X., Xu, Z., Zhang, Y. & Xie, Z. Anesthetic isoflurane increases phosphorylated tau levels mediated by caspase activation and Aβ generation. PLoS ONE 7, e39386 (2012).
Palotás, M. et al. Coronary artery bypass surgery provokes Alzheimer's disease-like changes in the cerebrospinal fluid. J. Alzheimers Dis. 21, 1153–1164 (2010).
Tang, J. X. et al. Human Alzheimer and inflammation biomarkers after anesthesia and surgery. Anesthesiology 115, 727–732 (2011).
Zhang, B. et al. Effects of anesthetic isoflurane and desflurane on human cerebrospinal fluid Aβ and τ level. Anesthesiology 119, 52–60 (2013).
Wu, X. et al. The inhalation anesthetic isoflurane increases levels of proinflammatory TNF-α, IL-6, and IL-1β. Neurobiol. Aging 33, 1364–1378 (2012).
This publication shows that the exposure of ageing animals to anaesthetics, without surgery, can increase the level of pro-inflammatory cytokines in the brain.
Cao, L., Li, L., Lin, D. & Zuo, Z. Isoflurane induces learning impairment that is mediated by interleukin 1β in rodents. PLoS ONE 7, e51431 (2012).
Li, Z. Q. et al. Activation of the canonical nuclear factor-κB pathway is involved in isoflurane-induced hippocampal interleukin-1β elevation and the resultant cognitive deficits in aged rats. Biochem. Biophys. Res. Commun. 438, 628–634 (2013).
Ye, X., Lian, Q., Eckenhoff, M. F., Eckenhoff, R. G. & Pan, J. Z. Differential general anesthetic effects on microglial cytokine expression. PLoS ONE 8, e52887 (2013).
Tian, Y., Guo, S., Guo, Y. & Jian, L. Anesthetic propofol attenuates apoptosis, Aβ accumulation, and inflammation induced by sevoflurane through NF-κB pathway in human neuroglioma cells. Cell. Mol. Neurobiol. 35, 891–898 (2015).
Avramescu, S. et al. Inflammation increases neuronal sensitivity to general anesthetics. Anesthesiology 124, 417–427 (2016).
Hemmings, H. C. et al. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol. Sci. 26, 503–510 (2005).
Cheng, V. Y. et al. α5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate. J. Neurosci. 26, 3713–3720 (2006).
Saab, B. J. et al. Short-term memory impairment after isoflurane in mice is prevented by the α5 γ-aminobutyric acid type A receptor inverse agonist L-655,708. Anesthesiology 113, 1061–1071 (2010).
Zurek, A. A. et al. Sustained increase in α5GABAA receptor function impairs memory after anesthesia. J. Clin. Invest. 124, 5437–5441 (2014).
This study demonstrates the role of α5GABAAR signalling in the pathogenesis of cognitive deficits.
Davidson, A. J. et al. Anesthesia and the developing brain: a way forward for clinical research. Paediatr. Anaesth. 25, 447–452 (2015).
Vutskits, L. General anesthetics in brain injury: friends or foes. Curr. Pharm. Des. 20, 4203–4210 (2014).
Cheng, B., Zhang, Y., Wang, A., Dong, Y. & Xie, Z. Vitamin C attenuates isoflurane-induced caspase-3 activation and cognitive impairment. Mol. Neurobiol. 52, 1580–1589 (2015).
Shih, J. et al. Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology 116, 586–602 (2012).
Cibelli, M. et al. Role of interleukin-1β in postoperative cognitive dysfunction. Ann. Neurol. 68, 360–368 (2010).
This seminal work demonstrates a role for systemic inflammation in the pathogenesis of postoperative cognitive dysfunction.
Terrando, N. et al. Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline. Proc. Natl Acad. Sci. USA 107, 20518–20522 (2010).
Terrando, N. et al. Resolving postoperative neuroinflammation and cognitive decline. Ann. Neurol. 70, 986–995 (2011).
Shu, Y. et al. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiol. Dis. 45, 743–750 (2012).
Anand, K. J. et al. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr. Res. 62, 283–290 (2007).
Zhang, X. et al. Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice. J. Neurosci. 33, 17737–17748 (2013).
Berger, M. et al. Postoperative cognitive dysfunction: minding the gaps in our knowledge of a common postoperative complication in the elderly. Anesthesiol. Clin. 33, 517–550 (2015).
Liimatainen, J. et al. Improved cognitive flexibility after aortic valve replacement surgery. Interact. Cardiovasc. Thorac. Surg. http://dx.doi.org/10.1093/icvts/ivw170 (2016).
Wilder, R. T. et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110, 796–804 (2009).
Flick, R. P. et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 128, e1053–e1061 (2011).
DiMaggio, C., Sun, L. S., Kakavouli, A., Byrne, M. W. & 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. 21, 286–291 (2009).
DiMaggio, C., Sun, L. S. & Li, G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth. Analg. 113, 1143–1151 (2011).
Ing, C. et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 130, e476–e485 (2012).
Bartels, M., Althoff, R. R. & Boomsma, D. I. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res. Hum. Genet. 12, 246–253 (2009).
Hansen, T. G. et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology 114, 1076–1085 (2011).
McCann, M. E. et al. Infantile postoperative encephalopathy: perioperative factors as a cause for concern. Pediatrics 133, e751–e757 (2014).
Vutskits, L., Davis, P. J., Hansen, T. G. & Davidson, A. Anesthetics and the developing brain: time for a change in practice? A pro/con debate. Paediatr. Anaesth. 22, 973–980 (2012).
Gleich, S. J. et al. Neurodevelopment of children exposed to anesthesia: design of the Mayo Anesthesia Safety in Kids (MASK) study. Contemp. Clin. Trials 41, 45–54 (2015).
Ing, C. H. et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology 120, 1319–1332 (2014).
Sun, L. S. et al. Feasibility and pilot study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. J. Neurosurg. Anesthesiol. 24, 382–388 (2012).
Davidson, A. J. et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 387, 239–250 (2016).
Sun, L. S. et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 315, 2312–2320 (2016).
Anand, K. J. et al. Can the human neonate mount an endocrine and metabolic response to surgery. J. Pediatr. Surg. 20, 41–48 (1985).
Taddio, A., Katz, J., Ilersich, A. L. & Koren, G. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 349, 599–603 (1997).
Müller, A. et al. Peri- and postoperative cognitive and consecutive functional problems of elderly patients. Curr. Opin. Crit. Care 22, 406–411 (2016).
Phillips-Bute, B. et al. Association of neurocognitive function and quality of life 1 year after coronary artery bypass graft (CABG) surgery. Psychosom. Med. 68, 369–375 (2006).
Steinmetz, J., Christensen, K. B., Lund, T., Lohse, N. & Rasmussen, L. S. Long-term consequences of postoperative cognitive dysfunction. Anesthesiology 110, 548–555 (2009).
Newman, M. F. et al. Report of the substudy assessing the impact of neurocognitive function on quality of life 5 years after cardiac surgery. Stroke 32, 2874–2881 (2001).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Association, 2013).
Monk, T. G. & Price, C. C. Postoperative cognitive disorders. Curr. Opin. Crit. Care 17, 376–381 (2011).
Robinson, T. N. et al. Postoperative delirium in the elderly: risk factors and outcomes. Ann. Surg. 249, 173–178 (2009).
Androsova, G., Krause, R., Winterer, G. & Schneider, R. Biomarkers of postoperative delirium and cognitive dysfunction. Front. Aging Neurosci. 7, 112 (2015).
Moller, J. T. et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 351, 857–861 (1998).
Abildstrom, H. et al. Cognitive dysfunction 1–2 years after non-cardiac surgery in the elderly. Acta Anaesthesiol. Scand. 44, 1246–1251 (2000).
Avidan, M. S. & Evers, A. S. The fallacy of persistent postoperative cognitive decline. Anesthesiology 124, 255–258 (2016).
Liu, L. L. & Leung, J. M. Predicting adverse postoperative outcomes in patients aged 80 years or older. J. Am. Geriatr. Soc. 48, 405–412 (2000).
Monk, T. G. et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 108, 18–30 (2008).
Koch, S. et al. Cerebral fat microembolism and cognitive decline after hip and knee replacement. Stroke 38, 1079–1081 (2007).
Puskas, F. et al. Intraoperative hyperglycemia and cognitive decline after CABG. Ann. Thorac. Surg. 84, 1467–1473 (2007).
Evered, L., Scott, D. A., Silbert, B. & Maruff, P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic. Anesth. Analg. 112, 1179–1185 (2011).
Williams-Russo, P., Sharrock, N. E., Mattis, S., Szatrowski, T. P. & Charlson, M. E. Cognitive effects after epidural versus general anesthesia in older adults. A randomized trial. JAMA 274, 44–50 (1995).
Rasmussen, L. S. et al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesthesiol. Scand. 47, 260–266 (2003).
Todd, M. M. Anesthetic neurotoxicity: the collision between laboratory neuroscience and clinical medicine. Anesthesiology 101, 272–273 (2004).
Anand, K. J. & Soriano, S. G. Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 101, 527–530 (2004).
Soriano, S. G., Anand, K. J., Rovnaghi, C. R. & Hickey, P. R. Of mice and men: should we extrapolate rodent experimental data to the care of human neonates? Anesthesiology 102, 866–868 (2005).
Vutskits, L. & Patel, P. Pushing the standards forward: in-depth monitoring of physiological parameters in anesthetized neonatal mice. Anesth. Analg. 119, 1029–1031 (2014).
Wu, B. et al. Physiological disturbance may contribute to neurodegeneration induced by isoflurane or sevoflurane in 14 day old rats. PLoS ONE 9, e84622 (2014).
Zhang, B. et al. The inhalation anesthetic desflurane induces caspase activation and increases amyloid β-protein levels under hypoxic conditions. J. Biol. Chem. 283, 11866–11875 (2008).
Jevtovic-Todorovic, V. & Olney, J. W. PRO: anesthesia-induced developmental neuroapoptosis: status of the evidence. Anesth. Analg. 106, 1659–1663 (2008).
Fitzgerald, M. The development of nociceptive circuits. Nat. Rev. Neurosci. 6, 507–520 (2005).
Clancy, B., Finlay, B. L., Darlington, R. B. & Anand, K. J. Extrapolating brain development from experimental species to humans. Neurotoxicology 28, 931–937 (2007).
Workman, A. D., Charvet, C. J., Clancy, B., Darlington, R. B. & Finlay, B. L. Modeling transformations of neurodevelopmental sequences across mammalian species. J. Neurosci. 33, 7368–7383 (2013).
Bohnen, N. I., Warner, M. A., Kokmen, E. & Kurland, L. T. Early and midlife exposure to anesthesia and age of onset of Alzheimer's disease. Int. J. Neurosci. 77, 181–185 (1994).
Bohnen, N. I., Warner, M. A., Kokmen, E., Beard, C. M. & Kurland, L. T. Alzheimer's disease and cumulative exposure to anesthesia: a case-control study. J. Am. Geriatr. Soc. 42, 198–201 (1994).
Lee, T. A., Wolozin, B., Weiss, K. B. & Bednar, M. M. Assessment of the emergence of Alzheimer's disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. J. Alzheimers Dis. 7, 319–324 (2005).
Chen, C. W. et al. Increased risk of dementia in people with previous exposure to general anesthesia: a nationwide population-based case-control study. Alzheimers Dement. 10, 196–204 (2014).
Chen, P. L. et al. Risk of dementia after anaesthesia and surgery. Br. J. Psychiatry 204, 188–193 (2014).
Gasparini, M. et al. A case-control study on Alzheimer's disease and exposure to anesthesia. Neurol. Sci. 23, 11–14 (2002).
Avidan, M. S. et al. Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. Anesthesiology 111, 964–970 (2009).
Aiello Bowles, E. J. et al. Anesthesia exposure and risk of dementia and Alzheimer's disease: a prospective study. J. Am. Geriatr. Soc. 64, 602–607 (2016).
Seitz, D. P., Reimer, C. L. & Siddiqui, N. A review of epidemiological evidence for general anesthesia as a risk factor for Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 47, 122–127 (2013).
Terrando, N., Eriksson, L. I. & Eckenhoff, R. G. Perioperative neurotoxicity in the elderly: summary of the 4th International Workshop. Anesth. Analg. 120, 649–652 (2015).
Zhang, Y. et al. Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory. Ann. Neurol. 71, 687–698 (2012).
Zhang, Y. et al. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J. Biol. Chem. 285, 4025–4037 (2010).
Wang, H. et al. Isoflurane induces endoplasmic reticulum stress and caspase activation through ryanodine receptors. Br. J. Anaesth. 113, 695–707 (2014).
Zhang, G. et al. Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J. Neurosci. 28, 4551–4560 (2008).
Wei, H. et al. The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology 108, 251–260 (2008).
Wei, H. & Xie, Z. Anesthesia, calcium homeostasis and Alzheimer's disease. Curr. Alzheimer Res. 6, 30–35 (2009).
Yang, H. et al. Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology 109, 243–250 (2008).