|Year : 2020 | Volume
| Issue : 2 | Page : 149-155
Safety of anesthetic exposure on the developing brain – Do we have the answer yet?
Anju Gupta1, Shruti Gairola2, Nishkarsh Gupta2
1 Department of Anesthesiology, Pain and Critical Care, AIIMS, New Delhi, India
2 Department of Onco-Anesthesiology and Palliative Care, DRBRAIRCH, AIIMS, Delhi, India
|Date of Submission||22-Jul-2019|
|Date of Acceptance||31-Aug-2019|
|Date of Web Publication||15-Jun-2020|
Dr. Nishkarsh Gupta
437, Pocket A, Sarita Vihar, New Delhi - 110 076
Source of Support: None, Conflict of Interest: None
During the past two decades, a vast number of studies done on rodents and nonhuman primates have implicated general anesthetic exposure of developing brains in producing neurotoxicity leading to various structural and functional neurological abnormalities with cognitive and behavioral deficits later in life. However, it is still unclear whether these findings translate to children and whether single exposure to anesthesia in childhood can have long-term neuro-developmental risks. Considering the fact that a large number of healthy young children are undergoing elective surgery under general anesthesia globally, any such potential neurocognitive risk of pediatric anesthesia is a serious public health issue and is therefore important to understand. This review aims to assess the current preclinical and clinical evidence related to anesthetic neurotoxicity.
Keywords: Anesthesia, child, developing brain, neurotoxicity
|How to cite this article:|
Gupta A, Gairola S, Gupta N. Safety of anesthetic exposure on the developing brain – Do we have the answer yet?. J Anaesthesiol Clin Pharmacol 2020;36:149-55
|How to cite this URL:|
Gupta A, Gairola S, Gupta N. Safety of anesthetic exposure on the developing brain – Do we have the answer yet?. J Anaesthesiol Clin Pharmacol [serial online] 2020 [cited 2020 Oct 1];36:149-55. Available from: http://www.joacp.org/text.asp?2020/36/2/149/286774
| Introduction|| |
Neurotoxicity refers to a type of toxicity in which a chemical, physical, or biological substance produces harmful structural or functional effect on the neuroaxis at the peripheral or central level. Neurotoxin is an agent exposure which can cause alteration in the normal activity of nervous system, causing permanent or reversible damage to nervous tissue. Toxicity of any agent is directly related to its dose and is less dependent on its chemical properties. Neurocognitive functions are closely related to functions of specific neural pathways, cerebral regions, or cortical links in the substrate layers of brain or neural matrix at the molecular level in cell. A neurocognitive deficit can be defined as a lessening or damage of cognitive functions in these regions.
During the past two decades, a vast number of animal studies done on rodents and non-human primates have implicated general anesthetics in causing various structural and functional neurological abnormalities in developing animal brain with cognitive and behavioral deficits later in life, thereby engendering a big debate among the clinicians regarding their safety for young children. The first evidence on this aspect was from a rodent study that was published in 1999. The study concluded that blocking N-methylD-aspartate (NMDA) glutamate receptors even for a short span of few hours during later part of pregnancy or early newborn period could trigger widespread apoptosis and neurodegeneration in the immature rat brain, suggesting that the neurotransmitter glutamate which is excitatory in nature, acting through the NMDA receptors, may have a role in controlling neuronal survival. They suggested in the light of these findings that exposure to NMDA receptor blockers (many anesthetics) may have implication in various neurodevelopment diseases.
With the widespread use of general anesthetic agents in the vulnerable neonates and young children, both during surgery and nonsurgical interventions, their safety is a burning public health problem and has drawn interest of the general public, regulatory bodies, and the anesthesiologists globally. To address these issues in the United States, a partnership between International Anaesthesia Research Society and Food and Drug Administration (FDA), known as Smart Tots (Strategies for Mitigating Anesthesia-Related neurotoxicity in Tots), was formed. It works toward coordination and funding research toward safe delivery of anesthetic/sedatives to children enduring surgery. In a recent update regarding the use of anesthetic and sedation agents in pregnant woman and young kids, issued in April 2017, FDA has approved two label changes with regard to their use in the aforementioned population. The first change includes a notice mentioning that long duration or multiple exposures to these agents may potentially affect brain development in children <3 years. The second warning is added information to pregnancy and pediatric use section labels describing research pertaining to pregnant and young animals which have demonstrated that exposure to these anesthetic drugs for a duration of >3 h may lead to widespread neural loss in the developing brain with behavioral and learning deficits later in animal's life. This review aims to understand the impact of the issue concerning neurotoxicity of anesthetics in neonate and young children in the present day context, based on the clinical and nonclinical studies conducted so far.
| Development of Normal Human Brain|| |
Brain development follows a predetermined organized pattern [Figure 1] that correlates with functions that a newborn performs at various stages of development. The process of neurogenesis begins in the early weeks of gestation after conception. The majority of the cortical neurons develop and proliferate in germinal matrix and subventricular zone. Migration to their final destination in cortex ensues between weeks 12 and 20 of gestation. Rapid automated death of cells (apoptosis) happens from 24 weeks of gestation to 4 weeks after birth causing 50% reduction in the neurons. Although cortical neurons develop before birth, they are poorly linked. Synaptogenesis (proliferation and organization of neuronal synapses) starts at about 20th week of gestation and the number of synapsis reaches a peak at about 1–2 years of age. This period of massive burst of synapse formation is known as the “exuberant period.”[6-9] Regionally, specific loss of synaptic connections in the process of pruning occurs following this. The major indicators of developmental stage are sulcation and myelination. Myelination begins by the end of second trimester and continues at a much slower rate throughout life.
Neuroplasticity is the ability of the brain to change throughout life. Various stimuli travelling through sensory afferents to the brain before and after birth cause change in the neuronal function and their pathways. This process of neuroplasticity is double-edged sword as it increases the capability of the human brain, on one hand, but, on the other hand, makes it vulnerable to changes in environment.
Mechanisms of anesthetic neurotoxicity
A report based on the Salzburg Seminar discussed in detail the various mechanisms leading to anesthesia-induced neurotoxicity based on current evidence from human and animal studies. Several mechanisms have been proposed to be causal in anesthesia-induced neurotoxicity.
The developmental stage and the degree of anesthetic exposure (both the frequency of exposure and cumulative anesthetic dose) are the two significant factors that determine anesthetic neurotoxicity.
It is clear from animal models that anesthesia-induced neuroapoptosis or defective synaptic development occurs in phase of synaptogenesis. As a result, the local differences in neurotoxicity could be related to dissimilarity in synaptogenesis in different brain regions during its development.
Certain brain regions such as the hippocampal dentate gyrus and the subventricular zone undergo neurogenesis all throughout life. In the hippocampus, this process of neurogenesis is thought to be important for learning and memory. In an animal study, repeated exposure of isoflurane for 35 min every day for 4 days to young rodents resulted in impaired memories which turned out to be more pronounced with the growth of the animals. However, adult rodents did not show such impairment with similar exposures. Why this isoflurane-induced loss of stem cells is seen in the young but not seen in the adult brains is still not clear.
A primary cultured model of hippocampal neurons, used to study neurotoxicity, exposed to 1.4% isoflurane or 2μM propofol for 4 h was shown to cause significant reduction in synaptic density. At the cellular level, there is activation of Ras homolog gene family (RhoA) and the growth factor receptor p75. Administration of Pep5 (an inhibitor of p75 receptor) along with isoflurane reduces its effect on synaptogenesis.
Mitochondrial dysfunction and oxidative stress also promote anesthesia-induced neurotoxicity. Anesthetics and sedatives acting through GABAA receptor activation increase intracellular calcium, disturb the mitochondrial membrane potential, and ultimately lead to cell death., Anesthetic agents such as propofol, isoflurane (along with midazolam and nitrous oxide), and sevoflurane are shown to increase reactive oxygen species (ROS). Hence, one should avoid redundant hyperoxic ventilation or may use antioxidants under anesthesia to protect against anesthesia-induced neurotoxicity., Anesthetic preconditioning has been postulated to reduce oxidative stress and mitochondrial dysfunction in brain and heart due to production of subtoxic ROS and subsequent antioxidant gene expression.,,,
Nitrous oxide neurotoxicity is mediated by blocking of the NMDA receptors and increasing the plasma homocysteine levels. In a study, an 8-h exposure to nitrous oxide was shown to be associated with an eight-fold increase in blood homocysteine level., However, future research is needed to assess whether this effect is important for short- or long-term neurocognitive outcomes.
Glial cells, an important anesthetic target, play an important role during early phase of brain growth., Isoflurane impairs glial cytoarchitecture in immature astrocytes, which could impair morphological growth and proliferation.
Surgery by itself has an additive effect on anesthesia-induced neurotoxicity. Interleukin-1 beta (a key proinflammatory factor elevated during surgery) increases the surface expression of GABAA receptors on neurons and may increase neurotoxicity.
Isoflurane activates the complement cascade and inflammatory pathways in the absence of apoptosis or overt changes in the number or morphology of microglia. Hence, the anesthetic effect is much more complex than activation of apoptosis during synaptogenesis.,
Effect of in utero and maternal exposure to anesthetics
The recent past has seen a growing number of fetal intervention programs and cases. Some of these would require a prolonged duration of general anesthesia involving the use of significant concentrations of volatile anesthetics to maintain uterine quiescence and to anesthetize both the mother and the fetus. Another important concern is that such fetus is likely to undergo multiple surgical procedures after birth also and thereby are prone to repeated anesthetic exposures later in life. Exposure of fetal brain to significant levels of GABAnergic agents as a result of the anesthetic exposure can potentially increase the risk of neurodegenerative changes. In cases of general anesthesia to the mother, the present data on fetal well-being focus on the teratogenic effects during early gestation and APGAR scores along with acid-base status at or near term. There are very limited data on neurodevelopmental consequences on the fetus of the in utero anesthetic exposure., There are several mechanisms that collectively increase the susceptibility of the fetal brain to anesthetic neurotoxicity, that is, ease of transfer of most anesthetic agents across placenta due to their lipophilicity, relatively longer duration of general anesthesia required for such procedures,, higher concentrations of volatile agents that may be needed, and finally the high sensitivity of the neurodevelopment process of neurogenesis and neuronal migration to environmental influences.
Difficulty in assessing the toxic effects of anesthetic agents on human brain
In the past two decades, a large number of nonclinical and clinical trials have studied the neurotoxic effects of the anesthetics on the developing brain. There still exists a clinical equipoise with some studies showing a possible negative effect and others showing no effect. The dominant question regarding the translatability of the results of animal studies to human population remains unanswered. However, due to obvious ethical concerns, exposures cannot be performed prospectively, nor can the anesthetic exposure be given to children when not indicated, limiting our ability to get precise answers.
What is the evidence of harm related to anesthetic agent exposure till now?
Recently, a number of studies on the same subject have been published in humans [Table 1].[39-49] Most of these are retrospective cohort studies showing inconsistent results. Till date, only one large multicentric randomized controlled trial, the GAS Trial, has been done. In this trial, infants undergoing hernia repair prospectively received either sevoflurane anesthesia or awake regional anesthesia, and the risk for cognitive decline in sevoflurane-exposed children was assessed using a cognitive test battery at 2 years. The trial failed to identify any increased risk for negative cognitive outcomes in the exposed group. The 5-year follow-up data on GAS study are awaited. With the available evidence, a meaningful answer cannot be drawn regarding the impact of age on neurotoxicity of anesthetic agents. The most vulnerable period or the age beyond which anesthetic exposure can be safe remains unknown. This is important to know so that elective surgeries can be postponed till the time beyond which anesthetic exposure is considered to be safe.
|Table 1: Clinical studies on the effects of anesthetic agents in childhood on neurological outcomes|
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Framework for studying anesthetic neurotoxicity
In vitro andin vivo research conducted in animals have suggested that exposure to anesthetics leads to structural impairments in brain structure by the process of increased apoptosis, decreased neurogenesis, synaptogenesis, and alterations in dendritic spine architecture and other undefined biological mechanisms. These collectively lead to neurotoxicity which manifests as adverse health effects in the form of neurocognitive dysfunctions and functional impairment.,, A conceptual framework [Figure 2] for studying neurotoxicity caused due to anesthetics was suggested by Guohua Li. To extrapolate these results from preclinical studies and analyze data from clinical studies, a wide range of end points including abnormalities in behavior and learning, performance in school, direct neuropsychological testing, and motor performance have been used.
Limitation of using preclinical evidence for studying anesthetic neurotoxicity
Animal studies by design are uniform unlike human studies where there is variability in exposure times and ages during exposure. Development of neurological abilities such as language, skills, intelligence, and academic performance takes a long period in humans, and so it is difficult to model these in animals. Language development may be especially susceptible to anesthetic exposure during infancy and toddler years., This aspect cannot be reasonably tested in preclinical studies. In addition, the developmental stages of rodents and even primates do not exactly parallel the corresponding human phases and there can be considerable lag in the various milestones, making a sound comparison difficult.
Anesthetic neuropharmacology, neurotoxicity, and neuroplasticity
Alcohol fetal syndrome shares many features in common with the apoptosis induced by anesthetics and sedatives. The possibility of long-term effect of anesthetic exposures on developing brain had been explored as an extension of animal research into occupational exposures and fetal alcohol syndromes., Various important aspects of anesthetic-induced neurotoxicity include the following given below.
Effect of exposure time
In both human and animal studies with exposure time of less than 1 h, the ratio of positive-to-negative studies ranged between 40% and 50%. Positive studies were the ones where at least one abnormality, even transiently, was reported and negative studies were those which did not identify any abnormal structural and/or functional outcome. For exposure times of more than 3 h, the ratio exceeded 80%. In line with these findings, many recent studies including only randomized controlled trial have not demonstrated any significant difference between children with a single brief exposure in early childhood or no exposure. Similarly, the PANDA study did not show any differences in IQ between siblings with and without anesthesia exposure of 20–240 min (median duration of 80 min). In a recent cohort study from Western Australia in 2608 children around 10 years of age, extensive neurobehavioral testing was done. It was seen that 321 children who were anesthetized and underwent surgery before 3 years of age had more probability of having defective language and abstract reasoning compared with unexposed children. However, it was noteworthy that more than one-third of them underwent surgery which lasted less than 15 min. Furthermore, this subset of population is known to suffer from later language and learning problems due to the primary disease, thereby raising doubts on the reliability of the results.
Effect of number of anesthetic exposures
There is wide variability in the results of studies done on this topic with some studies reporting functional and structural brain alterations following single anesthesia exposur,, while others reporting increased risk only with multiple exposure, and some reporting no negative results. However, multiple exposures of anesthesia have been consistently found to be linked with later learning disabilities. This may be related to the cumulated dose of exposure or the actual number of times the child got anesthetized. In a study by Wilder et al., single exposure did not increase the risk of cognitive impairment in 449 children studied, while more than one incidence of anesthesia exposure directly correlated with later learning disabilities among 144 children. Another study by Glatz et al. also observed proportionately worse school performance with higher episodes of anesthesia exposures. Limitations of these studies are that confounding variables are likely to increase with increasing number of surgical procedures. In addition, the duration of procedures was not analyzed.
Age during exposure and outcome
In most of the animal studies, immature stages of human brain development in antenatal period showed intense vulnerability to anesthetics. Interestingly, studies on humans and animals beyond the prenatal period did not show decline in positive studies with increasing age, during exposure as would be expected, based on the above findings. We cannot conclusively refer to a safe age after which anesthetic can be safely administered.
Two clinical studies on the preterm infants in neonatal intensive care unit examined the effects of exposure to long-standing sedatives which could not demonstrate any impaired cognition at 2—5 years following exposure to sedatives., The PANDA study was a large-scale multisite, ambi-directional sibling matched cohort study that included siblings within 36 months of age and assessed neurocognitive and behavioral outcomes prospectively in children at 8–15 years of age to ensure neurocognitive impairment if any. The data on anesthesia exposure were assessed retrospectively. They found no statistically significant difference in full-scale IQ score (mean difference of 0.2 IQ points) between siblings with and without single anesthesia exposure before 3 years of age. The secondary outcomes (mean scores of memory, language, attention, executive function, visuospatial function, motor and processing speed, or behavior) were also comparable.
Future direction for research
The impact of different anesthetic agents and the dosages on the neurodevelopment varies and safe thresholds need to be determined. The exposure time threshold also needs to be ascertained to know the “safe” time limits within which procedures can be performed under anesthesia. This will help in planning whether the surgery can be done in a single sitting or multiple. In addition, if multiple exposures are found to have increased risk, then procedures could be performed jointly at the cost of increasing exposure duration. The impact of surgery and pain vis-à-vis the neurotoxicity on the developing human brain needs to be assessed.
| Conclusion|| |
The current animal and human literature regarding anesthetic neurotoxicity is largely inconclusive and insufficient to make unambiguous recommendation regarding the safety of their use for neonates or older children. Further research is required to clearly identify the type of anesthetic agent and techniques, the threshold for age, and duration of exposure which can be clearly defined as safe for this vulnerable patient population. Till that time, there is no indication for pediatric anesthesiologists to modify their routine practice other than adopting various mitigating strategies.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Cunha-Oliveira T, Rego AC, Oliveira CR. Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs. Brain Res Rev 2008;58:192-208.
Blazer D. Commentary: Neurocognitive disorders in DSM-5. Am J Psychiatry 2013;170:585-7.
Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, et al
. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4.
U. S. Food and Drug Administration (FDA), Drug Safety Communication (cited 27-04-2017): FDA approves label changes for use of general anesthetic and sedation drugs in young children. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm554634.htm
. [Last accessed on 2019 Oct 11].
Tymofiyeva O, Hess CP, Xu D, Barkovich AJ. Structural MRI connectome in development: Challenges of the changing brain. Br J Radiol 2014;87:20140086.
Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth 2010;105(Suppl 1):i61-8.
Todd MM. Anesthetic neurotoxicity: The collision between laboratory neuroscience and clinical medicine. Anesthesiology 2004;1001:272-3.
Anand KJ, Soriano SG. Anesthetic agents and the immature brain: Are these toxic or therapeutic? Anesthesiology 2004;101:527-30.
Johnson MH. Functional brain development in humans. Nat Rev Neurosci 2001;2:475-83.
Vutkits L, Davies PJ, Hansen TG. Anesthetic and the developing brain: Time for a change in practice? A pro/con debate. Pediatr Anesth 2012;22:973-80.
Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, et al
. Anaesthetic neurotoxicity and neuroplasticity: An expert group report and statement based on the BJA Salzburg seminar. Br J Anaesth 2013;111:143-51.
Yon 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;135:815-27.
Zhu C, Gao J, Karlsson N, Li Q, Zhang Y, Huang Z, 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 Metab2010;30:1017-30.
Head 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;110:813-25.
Zhang Y, Dong Y, Wu X, Lu Y, Xu Z, Knapp A, et al
. The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem 2010;285:4025-37.
Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, et al
. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 2011;115:992-1002.
Boscolo A, Starr JA, Sanchez V, Lunardi N, DiGruccio MR, Ori C, 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 2012;45:1031-41.
Saugstad OD. Hyperoxia in the term newborn: More evidence is still needed for optimal oxygen therapy. Acta Paediatr Suppl 2012;101:34-8.
Wang C, Zhang X, Liu F, Paule MG, Slikker W. Anesthetic-induced oxidative stress and potential protection. Sci World J 2010;10:1473-82.
Pravdic D, Sedlic F, Mio Y, Vladic N, Bienengraeber M, Bosnjak ZJ. Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein Kinase C-epsilon-mediated pathway. Anesthesiology 2009;111:267-74.
Sepac A, Sedlic F, Si-Tayeb K, Lough J, Duncan SA, Bienengraeber M, et al
. Isoflurane preconditioning elicits competent endogenous mechanisms of protection from oxidative stress in cardiomyocytes derived from human embryonic stemcells. Anesthesiology 2010;113:906-16.
Stary CM, Tsutsumi YM, Patel PM, Head BP, Patel HH, Roth DM. Caveolins: Targeting pro-survival signaling in the heart and brain. Front Physiol 2012;3:393.
Yang Q, Dong H, Deng J, Wang Q, Ye R, Li X,et al
. Sevoflurane preconditioning induces neuroprotection through reactive oxygen species-mediated up-regulation of antioxidant enzymes in rats. Anesth Analg 2011;112:931-7.
Nagele P, Metz LB, Crowder CM. Nitrous oxide (N2O) requires the N
-methyl-d-aspartate receptor for its action in Caenorhabditis elegans
. Proc Natl Acad Sci USA 2004;101:8791-6.
Nagele P, Tallchief D, Blood J, Sharma A, Kharasch ED. Nitrous oxide anesthesia and plasma homocysteine in adolescents. Anesth Analg 2011;113:843-8.
Schummers J, Yu H, Sur M. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 2008;320:1638-43.
Thrane AS, RangrooThrane V, Zeppenfeld D, Lou N, Xu Q, Nagelhus EA,et al
. General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex. Proc Natl Acad Sci USA 2012;109:18974-9.
Shu Y, Zhou Z, Wan Y, Sanders RD, Li M, Pac-Soo CK,et al
. Nociceptive stimuli enhance anesthetic-induced neuroapoptosis in the rat developing brain. Neurobiol Dis 2012;45:743-50.
Wang DS, Zurek AA, Lecker I, Yu J, Abramian AM, Avramescu S,et al
. Memory deficits induced by inflammation are regulated by alpha5-subunit-containing GABA-A receptors. Cell Rep 2012;2:488-96.
Boulanger LM. Immune proteins in brain development and synaptic plasticity. Neuron 2009;64:93-109.
Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N,et al
. The classical complement cascade mediates CNS synapse elimination. Cell 2007;131:1164-78.
Rollins MD, Rosen MA. Anesthesia for fetal intervention and surgery. In: Gregory GA, Andropoulos DB, editors. Pediatric Anesthesia. 5 ed. Oxford: Wiley-Blackwell; 2012. p. 444-74.
Littleford J. Effects on the fetus and newborn of maternal analgesia and anesthesia: A review. Can J Anaesth 2004;51:586-609.
Cheek TG, Baird E. Anesthesia for nonobstetric surgery: Maternal and fetal considerations. Clin Obstet Gynecol 2009;52:535-45.
Li Y, Liang G, Wang S, Meng Q, Wang Q, Wei H. Effects of fetal exposure to isoflurane on postnatal memory and learning in rats. Neuropharmacology 2007;53:942-50.
Tran KM. Anesthesia for fetal surgery. SeminFetal Neonatal Med 2010;15:40-5.
Van De Velde M, De Buck F. Anesthesia for non-obstetric surgery in the pregnant patient. Minerva Anestesiol 2007;73:235-40.
Lin EP, Lee JR, Lee CS, Deng M, Loepke AW. Do anesthetics harm the developing human brain? An integrative analysis of animal and human studies. Neurotoxicol Teratol 2017;60:117-28.
Hansen TG, Pedersen JK, Henneberg SW, Pedersen DA, Murray JC, Morton NS,et al
. Academic performance in adolescence after inguinal hernia repair in infancy: A nationwide cohort study. Anesthesiology 2011;114:1076-85.
Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: No evidence for a causal relationship. Twin Res Hum Genet 2009;12:246-53.
Fan Q, Cai Y, Chen K, Li W. Prognostic study of sevoflurane-based general anesthesia on cognitive function in children. J Anesth 2013;27:493-9.
Stratmann G, Lee J, Sall JW, Lee BH, Alvi RS, Shih J, et al
. Effect of general anesthesia in infancy on long-term recognition memory in humans and rats. Neuropsychopharmacology 2014;39:2275-87.
Taghon TA, Masunga AN, Small RH, Kashou NH. A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia. Paediatr Anaesth 2015;25:239-46.
Backeljauw B, Holland SK, Altaye M, Loepke AW. Cognition and brain structure following early childhood surgery with anesthesia. Pediatrics 2015;136:e1-12.
Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, et al
. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 2016;315:2312-20.
Clausen NG, Pedersen DA, Pedersen JK, Moller SE, Grosen D, Wehby GL, et al
. Oral clefts and academic performance in adolescence: The impact of anesthesia-related neurotoxicity, timing of surgery, and type of oral clefts. Cleft Palate-Craniofac J 2017;54:371-80.
Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G,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 2016;387:239-50.
Hu D, Flick RP, Zaccariello MJ, Colligan RC, Katusic SK, Schroeder DR,et al
. Association between exposure of young children to procedures requiring general anesthesia and learning and behavioral outcomes in a population-based birth cohort. Anesthesiology 2017;127:227-40.
Glatz P, Sandin RH, Pedersen NL, Bonamy AK, Eriksson LI, Granath F. Association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr 2017;171:e163470.
Davidson AJ, Mc Cann ME, Morton NS, Myles PS. Anesthesia and outcome after neonatal surgery: The role for randomized trials. Anesthesiology 2008;109:941-4.
Sanders RD, Hassell J, Davidson AJ, Robertson NJ, MaD. Impact of anaesthetics and surgery on neurodevelopment: An update. BrJAnaesth 2013;110(Suppl 1):i53-72.
Psaty BM, Platt R, Altman RB. Neurotoxicity of generic anesthesia agents in infants and children: An orphan research question in search of a sponsor. JAMA 2015;313:1515-6.
Ney JW, Farber NB, WozniakDF, Jevtovic-Todorovic V, Ikonomidou C. Environmental agents that have the potential to triggermassive apoptotic neurodegeneration in the developing brain. Environ Health Perspect 2000;108:383-8.
Uemura E, Bowman RE. Effects of halothane on cerebral synaptic density. Exp Neurol 1980;69:135-42.
Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS,et al
. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012;130:e476-85.
WilderRT, FlickRP, SprungJ, Katusic SK, Barbaresi WJ, Mickelson C, et al
. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009;110:796-804.
Filan PM, Hunt RW, Anderson PJ, DoyleLW, Inder TE. Neurologic outcomes in very preterm infants undergoing surgery. J Pediatr 2012;160:409-14.
Rozé JC, Denizot S, Carbajal R, Ancel PY, Kaminski M, Arnaud C,et al
. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome invery preterm infants: Results from the EPIPAGE cohort. Arch Pediatr Adolesc Med 2008;162:728-33.
[Figure 1], [Figure 2]