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Anesthesiology:
Special Article

Anesthetic Agents and the Immature Brain: Are These Toxic or Therapeutic?

Anand, Kanwaljeet J.S. M.B.B.S., D. Phil.*; Soriano, Sulpicio G. M.D.†

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ABOUT 1.5 million fetuses or newborns are exposed to anesthetic agents each year.1 After their initial report in Science2 suggesting that anesthetic drugs such as nitrous oxide, ketamine or other N-methyl-d-aspartate receptor antagonists lead to enhanced apoptosis in immature neurons, Olney et al. have reported that newborn rats exposed to commonly used anesthetic agents (isoflurane, midazolam, and nitrous oxide) also develop neurodegenerative changes in multiple areas of the brain, associated with long-term deficits in learning and memory.3 The same investigators have reported similar neurodegenerative changes in rat pups exposed to other anesthetic agents, anticonvulsant drugs, or ethanol2,4–7 and voiced their “concern that agents used in pediatric and obstetrical medicine for purposes of sedation, anesthesia, and seizure management may cause apoptotic neuronal death in the developing human brain.”5 This has led to public outcry over the long-term effects of anesthesia or sedation given to pregnant women or to newborn infants requiring surgical operations after birth.8–13 Calls for avoiding these agents in newborns raises the specter of surgical procedures being performed with minimal or no anesthesia, as was routine practice 20 years ago.14
Accumulating data on the development of the pain-responsive15–19 and stress-responsive20–22 systems in the developing brain, together with increases in stress responses, morbidity, and mortality in lightly anesthetized neonates,23–25 have led to the routine use of anesthesia and postoperative analgesia even for critically ill newborns.26,27 Are the findings of Olney et al. significant enough to withhold anesthesia from neonates undergoing surgical operations or other invasive procedures? This issue needs to be addressed urgently, especially as no clinician would like to withhold anesthetics during a surgical procedure nor would any wish to expose their neonatal patients to potentially neurotoxic drugs.
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Anesthetic Agents and Neurodegenerative Mechanisms

Brain development in preterm and term neonates is characterized by naturally occurring neuronal death by apoptotic mechanisms.28–30 The cellular expression of regulator protein Bcl-2 and effector enzyme caspase-3 appear to mediate the increased vulnerability to neuronal apoptosis in the immature brain,31,32 which affects more than 50 percent of cortical neurons after 28 weeks of human gestation.28 An increased vulnerability to apoptosis is not limited to neurons but extends to immature oligodendroglia and astrocytes as well, particularly following free radical injury.33,34 Immature neurons are also susceptible to excitotoxic damage because of an increased magnitude of ligand-gated calcium currents mediated via excitatory N-methyl-d-aspartate receptors,35–37 ultimately leading to neuronal excitotoxic damage.38,39
Accentuated neurodegenerative mechanisms in the immature brain thus increase neuronal susceptibility to various metabolic events (hypoglycemia, hypoxia, infection, ischemia, seizures) or exposure to anesthetic agents.40 Anesthetic and anticonvulsant drugs that block N-methyl-d-aspartate receptors (e.g., ketamine) or activate γ-amino butyric acid-type A receptors (e.g., midazolam) consistently increase neuronal apoptosis in the neonatal brain,2–7 suggesting that the physiologic simulation of N-methyl-d-aspartate receptors is necessary for neuronal synaptogenesis, differentiation, and survival during development. Lack of N-methyl-d-aspartate receptor activation by glutamate decreases synaptogenesis and cell-to-cell interactions.41,42 Anesthetic agents directly suppress neuronal activation and also reduce extracellular concentrations of excitatory neurotransmitters,43 thereby reducing the developmental inputs to immature neurons.
In evaluating the clinical relevance of these findings, we must consider the major differences in complexity and adaptability between human and rodent brains and also the developmental differences between neonatal rats and humans.44,45 Additional methodological issues to be considered before extrapolating these results to neonatal anesthesia in humans include (a) a prolonged duration of exposure to anesthetic agents; (b) the nutritional and metabolic needs of neonates receiving general anesthesia; (c) the routine use of continuous respiratory, hemodynamic, and other forms of monitoring and support during anesthesia; (d) dose-related effects of certain anesthetic agents; and (e) divergent effects of anesthetic drugs given in the presence or absence of surgical pain or stress. Each of these issues is discussed below.
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Duration of Exposure to Anesthetic Drugs
Neurodegenerative changes in the developing brain occurred following prolonged exposure to anesthesia in neonatal rats,2,6 confirming earlier findings from exposure to halothane or N-methyl-d-aspartate receptor blockade.46,47 From a developmental perspective, this duration of exposure would be equivalent to producing general anesthesia for several weeks in the human neonate,44 which occurs rarely, if ever, in the clinical setting. Repeated ketamine injections increase neuronal cell death in multiple areas of the neonatal rat brain and lead to a significant decrease in weight gain.48 Rat pups receiving ketamine for 6–9 h exhibited poor feeding behavior and increased neurodegeneration, whereas single doses of ketamine did not affect weight gain or neuronal cell death. These studies suggest that prolonged exposure to anesthetic drugs may be an essential factor in this phenomenon.48 Although recent data presented at the annual meeting of the American Association for the Advancement of Science on February 14, 200449 suggest that brief exposure to alcohol or anesthetic drugs may also trigger two- to fourfold increases in neuronal apoptosis,50 it remains unclear whether these neurons would have died at later developmental stages and whether these transient increases in neuronal apoptosis have any long-term consequences.
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Effects of Malnutrition on the Immature Brain
Rodent pups do not suckle during or after general anesthesia. Decreased weight gain following prolonged ketamine anesthesia points to the role of nutrition in early brain development.48 Clinical and experimental research have linked malnutrition to decreased brain growth and learning disabilities,51–53 although Olney et al. do not report the nutritional support given or weight gain data from their experiments.2–7 The identification of milk in the gastric contents of neonatal rat pups does not imply adequate nutrition because both general anesthesia and breast milk significantly delay gastric emptying in neonates.54 Human neonates routinely receive nutritional support and metabolic monitoring in the perioperative period, thus minimizing the risks for hypoglycemia and impaired nutrition.
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Anesthesia and Cerebral Oxygen Delivery
Anesthetic drugs suppress brain activity but also depress circulation and respiration in a dose-dependent manner, leading to decreased cerebral perfusion and hypoxia. Administration of anesthetic drugs to human neonates is accompanied by continuous monitoring of blood pressure, heart rate, and oxygen saturations, with multiple therapies aimed to optimize these parameters. Hypoxia and ischemia during prolonged anesthesia could easily trigger widespread neurodegeneration in the immature brain,55–57 given the lack of similar monitoring or support in newborn rat pups.2–7
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Dose-Related Effects of Anesthetic Agents
Anesthetic drugs also have dose-dependent cellular effects. For example, ketamine acts as an antiinflammatory agent at subanesthetic concentrations (0.1–0.5 μg/ml),58,59 whereas higher concentrations (50–200 μg/ml) produce a nonspecific cytostatic effect.60 High doses of ketamine may also promote seizures,61 a property shared by other anesthetic agents.62 The ketamine doses used by Ikonomidou et al.2 (140 mg/kg) would be expected to produce cytostatic or epileptogenic effects in neonatal rats, which may significantly contribute to the neuronal apoptosis63,64 reported in these studies.
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Anesthesia With and Without Painful Stimulation
Prolonged anesthesia produces a loss of developmentally important sensory inputs during this critical window, a condition that is perhaps not dissimilar from maternal separation.65 Repetitive pain and maternal separation in newborn rat pups lead to long-term changes in behavior,20,66,67 some of which are prevented by analgesic therapy.68,69 These data suggest that the long-term effects of analgesic/anesthetic drugs would depend on whether they are given in the presence or absence of painful stimulation. The clinical use of anesthetic agents occurs during painful stimulation, but Olney et al. administered anesthesia without any painful stimulation. Based on the neuronal stimulation hypothesis,42 we speculate that painful stimuli during surgery activate N-methyl-d-aspartate and other excitatory receptors in the immature brain and that therapeutic doses of anesthetic drugs will reduce extreme degrees of neuronal excitation.40,70 Thus, the effects of surgery without anesthesia as well as the effects of anesthesia without surgery may be detrimental to the developing brain. Clinical extrapolation from these rodent models2,5,6 requires that the experimental conditions should be similar to those associated with surgical anesthesia in human neonates.
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Consequences of Withholding Anesthesia/Analgesia
In addition to humanitarian concerns, multiple lines of evidence support the necessity of adequate anesthesia in term or preterm neonates undergoing surgery. Short-term consequences of withholding anesthetic agents during neonatal surgery include an increased incidence of intraoperative and postoperative complications,23–25,71 leading to poor surgical outcomes.71–75 Long-term consequences of repetitive and prolonged pain in the neonatal period include prolonged changes in pain sensitivity and pain processing,76–79 as well as a variety of neurodevelopmental, behavioral, and cognitive deficits manifesting in later childhood.40,74,80–82 The evidence for improved clinical and developmental outcomes highlighting the importance of adequate anesthesia and pain control in the surgical neonate continues to mount, which must be weighed carefully against the recent experimental data showing the neurotoxic effects of anesthetic agents.
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Conclusions
There is no doubt that prolonged exposure of newborn rat pups to anesthetic and anticonvulsant drugs leads to accelerated neurodegeneration and long-term behavioral deficits. Similarly, preterm and term neonates subjected to prolonged pain and surgical stress are also at risk for long-term adverse outcomes. Further investigations in this area may consider an experimental design in which the neurobiological and clinical effects of anesthesia with and without surgery are compared to increase its relevance to the clinical situation. Clearer understanding of the mechanisms by which exposures to pain/stress or prolonged anesthesia in the perinatal period can alter the survival or development of immature neurons and glia may prevent some long-term neurobehavioral abnormalities in humans. In the meantime, clinicians should administer anesthetic agents to newborn infants or pregnant mothers but avoid prolonged periods of anesthetic exposure. The experimental findings of Olney et al. are certainly sound but it may be premature to apply them to clinical settings at this time. Alleviation of pain and stress during the perinatal period should remain an essential clinical goal until further research defines the clinical importance of these results.
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Dallimore, D; Anderson, BJ; Short, TG; Herd, DW
Pediatric Anesthesia, 18(8): 708-714.
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Annals of Emergency Medicine
Ketamine and Neurotoxicity: Clinical Perspectives and Implications for Emergency Medicine
Green, SM; Cote, CJ
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Toxicological Sciences
Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro
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Archives of Pediatrics & Adolescent Medicine
Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants - Results from the EPIPAGE cohort
Roze, JC; Denizot, S; Carbajal, R; Ancel, PY; Kaminski, M; Arnaud, C; Truffert, P; Marret, S; Matis, J; Thiriez, G; Cambonie, G; Andre, M; Larroque, B; Breart, G
Archives of Pediatrics & Adolescent Medicine, 162(8): 728-733.

Current Pain and Headache Reports
Strategies for the Prevention and Management of Neonatal and Infant Pain
Harrison, D; Yamada, J; Stevens, B
Current Pain and Headache Reports, 14(2): 113-123.
10.1007/s11916-009-0091-0
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Seminars in Fetal & Neonatal Medicine
Long-term consequences of pain in human neonates
Grunau, RE; Holsti, L; Peters, JWB
Seminars in Fetal & Neonatal Medicine, 11(4): 268-275.
10.1016/j.siny.2006.02.007
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Chinese Medical Journal
Effects of ketamine and midazolam on morphology of dendritic spines in hippocampal CA1 region of neonatal mice
Tan, H; Ren, RR; Xiong, ZQ; Wang, YW
Chinese Medical Journal, 122(4): 455-459.
10.3760/cma.j.issn.0366-6999.2009.04.0018
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Anesthesia and Analgesia
Revising a dogma: Ketamine for patients with neurological injury?
Himmelseher, S; Durieux, ME
Anesthesia and Analgesia, 101(2): 524-534.
10.1213/01.ANE.0000160585.43587.5B
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Pediatrics
Summary proceedings from the neonatal pain-control group
Anand, KJS; Aranda, JV; Berde, CB; Buckman, S; Capparelli, EV; Carlo, W; Hummel, P; Johnston, CC; Lantos, J; Tutag-Lehr, V; Lynn, AM; Maxwell, LG; Oberlander, TF; Raju, TNK; Soriano, SG; Taddio, A; Walco, GA
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Anesthesia and Analgesia
Anesthetics as neuroprotectants/neurotoxins
Warner, DS
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Pediatric Research
Ketamine reduces the cell death following inflammatory pain in newborn rat brain
Anand, KJS; Garg, S; Rovnaghi, CR; Narsinghani, U; Bhutta, AT; Hall, RW
Pediatric Research, 62(3): 283-290.

Anesthesia and Analgesia
Isoflurane-induced neuronal degeneration: An evaluation in organotypic hippocampal slice cultures
Wise-Faberowski, L; Zhang, HT; Ing, R; Pearlstein, RD; Warner, DS
Anesthesia and Analgesia, 101(3): 651-657.
10.1213/01.ane.0000167382.79889.7c
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Pediatric Anesthesia
Remifentanil for sedation and analgesia in a preterm neonate with respiratory distress syndrome
Silva, YPE; Gomez, RS; Barbosa, RF; Silva, ACSE
Pediatric Anesthesia, 15(): 993-996.
10.1111/j.1460-9592.2005.01666.x
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Anesthesia and Analgesia
Increasing the Duration of Isoflurane Anesthesia Decreases the Minimum Alveolar Anesthetic Concentration in 7-Day-Old but Not in 60-Day-Old Rats
Stratmann, G; Sall, JW; Eger, EI; Laster, MJ; Bell, JS; May, LDV; Eilers, H; Krause, M; Van der Heusen, F; Gonzalez, HE
Anesthesia and Analgesia, 109(3): 801-806.
10.1213/ane.0b013e3181aff364
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Acta Paediatrica
Promoting shorter duration of ventilator treatment decreases the number of painful procedures in preterm infants
Axelin, A; Ojajarvi, U; Viitanen, J; Lehtonen, L
Acta Paediatrica, 98(): 1751-1755.
10.1111/j.1651-2227.2009.01446.x
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Journal of Cardiothoracic and Vascular Anesthesia
Neuroprotection by Ketamine: A Review of the Experimental and Clinical Evidence
Hudetz, JA; Pagel, PS
Journal of Cardiothoracic and Vascular Anesthesia, 24(1): 131-142.
10.1053/j.jvca.2009.05.008
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Brain Pathology
Clinical anesthesia causes permanent damage to the fetal guinea pig brain
Rizzi, S; Carter, LB; Ori, C; Jevtovic-Todorovic, V
Brain Pathology, 18(2): 198-210.
10.1111/j.1750-3639.2007.00116.x
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Seminars in Fetal & Neonatal Medicine
The offer they can't refuse: parents and perinatal treatment decisions
Harrison, H
Seminars in Fetal & Neonatal Medicine, 13(5): 329-334.
10.1016/j.siny.2008.03.004
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Pediatric Anesthesia
Bispectral index in pediatrics: fashion or a new tool?
Murat, I; Constant, I
Pediatric Anesthesia, 15(3): 177-180.
10.1111/j.1460-9592.2004.01564.x
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Presse Medicale
Does anesthesia affect cerebral development?
Vutskits, L; Habre, W
Presse Medicale, 38(): 1591-1596.
10.1016/j.lpm.2009.07.013
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Pediatric Research
Use of Analgesic and Sedative Drugs in the NICU: Integrating Clinical Trials and Laboratory Data
Durrmeyer, X; Vutskits, L; Anand, KJS; Rimensberger, PC
Pediatric Research, 67(2): 117-127.

Anesthesia and Analgesia
Beyond Anesthetic Properties: The Effects of Isoflurane on Brain Cell Death, Neurogenesis, and Long-Term Neurocognitive Function
Stratmann, G; Sall, JW; May, LDV; Loepke, AW; Lee, MT
Anesthesia and Analgesia, 110(2): 431-437.
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Archives De Pediatrie
Pain in neonates: pharmacological treatment
Carbajal, R
Archives De Pediatrie, 13(2): 211-224.
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Pain
Pain activates cortical areas in the preterm newborn brain
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Acta Anaesthesiologica Scandinavica
Effects of anaesthetics on the developing brain - experimental results in animals
Suellen, WM
Acta Anaesthesiologica Scandinavica, 51(): 65-67.

Seminars in Fetal & Neonatal Medicine
Pain control: Opioid dosing, population kinetics and side-effects
Simons, SHP; Anand, KJS
Seminars in Fetal & Neonatal Medicine, 11(4): 260-267.
10.1016/j.siny.2006.02.008
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Anesthesia and Analgesia
Victims of our own success or quo vadis pediatric anesthesia?
Nichols, DG; Yaster, M
Anesthesia and Analgesia, 104(2): 255-257.
10.1213/01.ane.0000253549.28893.bc
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Anaesthesia, Pain, Intensive Care and Emergency: A.P.I.C.E
General anaesthesia and the developing brain
Jevtovic-Todorovic, V
Anaesthesia, Pain, Intensive Care and Emergency: A.P.I.C.E, (): 45-50.

Anesthesia and Analgesia
Neuroprotective strategies for the neonatal brain
Degos, V; Loron, G; Mantz, J; Gressens, P
Anesthesia and Analgesia, 106(6): 1670-1680.
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Annales Francaises D Anesthesie Et De Reanimation
Risks in paediatric anaesthesia
Murat, I; Humblot, A; Girault, L
Annales Francaises D Anesthesie Et De Reanimation, 28(): 666-670.
10.1016/j.annfar.2009.06.013
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Pediatric Anesthesia
Fundamentals of neuronal apoptosis relevant to pediatric anesthesia
Blaylock, M; Engelhardt, T; Bissonnette, B
Pediatric Anesthesia, 20(5): 383-395.
10.1111/j.1460-9592.2010.03291.x
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International Journal of Nursing Studies
Utilization of analgesics, sedatives, and pain scores in infants with a prolonged hospitalization: A prospective descriptive cohort study
Harrison, D; Loughnan, P; Manias, E; Johnston, L
International Journal of Nursing Studies, 46(5): 624-632.
10.1016/j.ijnurstu.2008.11.001
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Neurotoxicology
Clinical research approaches to studying pediatric anesthetic neurotoxicity
McCann, ME; Bellinger, DC; Davidson, AJ; Soriano, SG
Neurotoxicology, 30(5): 766-771.
10.1016/j.neuro.2009.02.013
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Anesthesia and Analgesia
The Young: Neuroapoptosis Induced by Anesthetics and What to Do About It
Creeley, CE; Olney, JW
Anesthesia and Analgesia, 110(2): 442-448.
10.1213/ANE.0b013e3181c6b9ca
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Acta Paediatrica
Anaesthetic neurotoxicity in rodents: is the ketamine controversy real ?
Bhutta, AT; Venkatesan, AK; Rovnaghi, CR; Anand, KJS
Acta Paediatrica, 96(): 1554-1556.
10.1111/j.1651-2227.2007.00436.x
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Pediatrics
Morphine, hypotension, and intraventricular hemorrhage
Anand, KJS; Hall, RW
Pediatrics, 117(1): 250-252.
10.1542/peds.2005-2250
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Pediatrics
The Newborn Drug Development Initiative - Introduction
Giacoia, GP; Birenbaum, DL; Sachs, HC; Mattison, DR
Pediatrics, 117(3): S1-S8.
10.1542/peds.2005-0620B
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British Journal of Anaesthesia
Distinct long-term neurocognitive outcomes after equipotent sevoflurane or isoflurane anaesthesia in immature rats
Ramage, TM; Chang, FL; Shih, J; Alvi, RS; Quitoriano, GR; Rau, V; Barbour, KC; Elphick, SA; Kong, CL; Tantoco, NK; Ben-Tzur, D; Kang, H; McCreery, MS; Huang, P; Park, A; Uy, J; Rossi, MJ; Zhao, C; Di Geronimo, RT; Stratmann, G; Sall, JW
British Journal of Anaesthesia, 110(): 39-46.
10.1093/bja/aet103
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Plos One
Effect of Propofol in the Immature Rat Brain on Short- and Long-Term Neurodevelopmental Outcome
Karen, T; Schlager, GW; Bendix, I; Sifringer, M; Herrmann, R; Pantazis, C; Enot, D; Keller, M; Kerner, T; Felderhoff-Mueser, U
Plos One, 8(5): -.
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CNS Neuroscience & Therapeutics
Preclinical Assessment of Ketamine
Wang, C; Liu, F; Patterson, TA; Paul, MG; Slikker, W
CNS Neuroscience & Therapeutics, 19(6): 448-453.
10.1111/cns.12079
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Anesthesiology
Of Mice and Men: Should We Extrapolate Rodent Experimental Data to the Care of Human Neonates?
Soriano, SG; Anand, KJ; Rovnaghi, CR; Hickey, PR
Anesthesiology, 102(4): 866-868.

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Anesthesiology
Behavior and Development in Children and Age at the Time of First Anesthetic Exposure
Kalkman, CJ; Peelen, L; Moons, KG; Veenhuizen, M; Bruens, M; Sinnema, G; de Jong, TP
Anesthesiology, 110(4): 805-812.
10.1097/ALN.0b013e31819c7124
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Anesthesiology
Effect of Hypercarbia and Isoflurane on Brain Cell Death and Neurocognitive Dysfunction in 7-day-old Rats
Stratmann, G; May, LD; Sall, JW; Alvi, RS; Bell, JS; Ormerod, BK; Rau, V; Hilton, JF; Dai, R; Lee, MT; Visrodia, KH; Ku, B; Zusmer, EJ; Guggenheim, J; Firouzian, A
Anesthesiology, 110(4): 849-861.
10.1097/ALN.0b013e31819c7140
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Anesthesiology
Clinically Relevant Concentrations of Propofol but Not Midazolam Alter In Vitro Dendritic Development of Isolated γ-Aminobutyric Acid-positive Interneurons
Vutskits, L; Gascon, E; Tassonyi, E; Kiss, JZ
Anesthesiology, 102(5): 970-976.

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Anesthesiology
Anesthesia-induced Developmental Neuroapoptosis: Does It Happen in Humans?
Olney, JW; Young, C; Wozniak, DF; Ikonomidou, C; Jevtovic-Todorovic, V
Anesthesiology, 101(2): 273-275.

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Anesthesiology
Anesthesia and Neurodevelopment in Children: Time for an Answer?
Sun, LS; Li, G; DiMaggio, C; Byrne, M; Rauh, V; Brooks-Gunn, J; Kakavouli, A; Wood, A; Coinvestigators of the Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Research Network,
Anesthesiology, 109(5): 757-761.
10.1097/ALN.0b013e31818a37fd
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European Journal of Anaesthesiology (EJA)
Liaisons dangereuses? General anaesthetics and long‐term toxicity in the CNS
Perouansky, M
European Journal of Anaesthesiology (EJA), 24(2): 107-115.
10.1017/S0265021506001165
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European Journal of Anaesthesiology (EJA)
Potentially toxic effects of anaesthetics on the developing central nervous system*
Gascon, E; Klauser, P; Kiss, JZ; Vutskits, L
European Journal of Anaesthesiology (EJA), 24(3): 213&hyhen;224.
10.1017/S0265021506002365
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Journal of Neurosurgical Anesthesiology
Isoflurane-induced Neuroapoptosis in the Developing Brain of Nonhypoglycemic Mice
Johnson, SA; Young, C; Olney, JW
Journal of Neurosurgical Anesthesiology, 20(1): 21-28.
10.1097/ANA.0b013e3181271850
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Journal of Neurosurgical Anesthesiology
Let's Not Throw the Baby Out With the Bath Water: Potential Neurotoxicity of Anesthetic Drugs in Infants and Children
Soriano, SG; Loepke, AW
Journal of Neurosurgical Anesthesiology, 17(4): 207-209.

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Pediatric Critical Care Medicine
Developmental neurotoxicity of sedatives and anesthetics: A concern for neonatal and pediatric critical care medicine?*
Loepke, AW
Pediatric Critical Care Medicine, 11(2): 217-226.
10.1097/PCC.0b013e3181b80383
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Pediatric Critical Care Medicine
Thinking about the neurotoxic effects of sedatives on the developing brain*
Soriano, SG
Pediatric Critical Care Medicine, 11(2): 306-307.
10.1097/PCC.0b013e3181c31804
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