Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-18T14:25:20.113Z Has data issue: false hasContentIssue false
  • English
  • Français

Potentially toxic effects of anaesthetics on the developing central nervous system*

Published online by Cambridge University Press:  01 March 2007

E. Gascon ,
P. Klauser ,
J. Z. Kiss  and
L. Vutskits
Get access

Summary

A growing body of experimental evidence suggests that anaesthetics, by influencing GABAergic and glutaminergic neural signalling, can have adverse effects on the developing central nervous system. The biological foundation for this is that gamma-aminobutyric acid and glutamate could act non-synaptically, in addition to their role in neurotransmission in the adult brain, in the regulation of neuronal development in the central nervous system. These neurotransmitters and their receptors are expressed from very early stages of central nervous system development and appear to influence neural progenitor proliferation, cell migration and neuronal differentiation. During the synaptogenetic period, pharmacological blockade of N-methyl-d-aspartate (NMDA)-type glutamate receptors as well as stimulation of GABAA receptors has been reported to be associated with increased apoptosis in the developing brain. Importantly, recent data suggest that even low, non-apoptogenic concentrations of anaesthetics can perturb neuronal dendritic development and thus could potentially lead to impairment of developing neuronal networks. The extrapolation of these experimental observations to clinical practice is of course very difficult and requires extreme caution as differences in drug concentrations and exposure times as well as interspecies variations are all important confounding variables. While clinicians should clearly not withhold anaesthesia based on current animal studies, these observations should urge more laboratory and clinical research to further elucidate this issue.

Keywords

ANAESTHESIAANAESTHETIC AGENTSAPOPTOSISDENDRITESGAMMA-AMINOBUTYRIC ACIDGLUTAMATENEUROTOXICITY
Type
Review Article
Information
European Journal of Anaesthesiology , Volume 24 , Issue 3 , March 2007 , pp. 213 - 224
Copyright
Copyright © European Society of Anaesthesiology 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Hobbs, AJ, Bush, GH, Downham, DY. Peri-operative dreaming and awareness in children. Anaesthesia 1988; 43: 560–562.CrossRefGoogle ScholarPubMed
2.Anand, KS. Relationships between stress responses and clinical outcome in newborns, infants, and children. Crit Care Med 1993; 21: S358–S359.CrossRefGoogle ScholarPubMed
3.Bouwmeester, NJ, Anand, KJ, van Dijk, M et al. . Hormonal and metabolic stress responses after major surgery in children aged 0–3 years: a double-blind, randomized trial comparing the effects of continuous versus intermittent morphine. Br J Anaesth 2001; 87: 390–399.CrossRefGoogle Scholar
4.van Lingen, RA, Simons, SH, Anderson, BJ, Tibboel, D. The effects of analgesia in the vulnerable infant during the perinatal period. Clin Perinatol 2002; 29: 511–534.CrossRefGoogle ScholarPubMed
5.Taddio, A, Shah, V, Gilbert-MacLeod, C, Katz, J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 2002; 288: 857–861.CrossRefGoogle ScholarPubMed
6.Tobiansky, R, Lui, K, Roberts, S, Veddovi, M. Neurodevelopmental outcome in very low birthweight infants with necrotizing enterocolitis requiring surgery. J Paediatr Child Health 1995; 31: 233–236.CrossRefGoogle ScholarPubMed
7.Chacko, J, Ford, WD, Haslam, R. Growth and neuro-developmental outcome in extremely-low-birth-weight infants after laparotomy. Pediatr Surg Int 1999; 15: 496–499.CrossRefGoogle Scholar
8.Represa, A, Ben-Ari, Y. Trophic actions of GABA on neuronal development. Trends Neurosci 2005; 28: 278–283.CrossRefGoogle ScholarPubMed
9.Waters, KA, Machaalani, R. NMDA receptors in the developing brain and effects of noxious insults. Neurosignals 2004; 13: 162–174.CrossRefGoogle ScholarPubMed
10.Nguyen, L, Rigo, JM, Rocher, V et al. . Neurotransmitters as early signals for central nervous system development. Cell Tissue Res 2001; 305: 187–202.CrossRefGoogle ScholarPubMed
11.Herlenius, E, Lagercrantz, H. Development of neurotransmitter systems during critical periods. Exp Neurol 2004; 190 (Suppl 1): S8–S21.CrossRefGoogle ScholarPubMed
12.Benitez-Diaz, P, Miranda-Contreras, L, Mendoza-Briceno, RV et al. . Prenatal and postnatal contents of amino acid neurotransmitters in mouse parietal cortex. Dev Neurosci 2003; 25: 366–374.CrossRefGoogle ScholarPubMed
13.Lujan, R, Shigemoto, R, Lopez-Bendito, G. Glutamate and GABA receptor signalling in the developing brain. Neuroscience 2005; 130: 567–580.CrossRefGoogle ScholarPubMed
14.McMahon, D. Chemical messengers in development: a hypothesis. Science 1974; 185: 1012–1021.CrossRefGoogle ScholarPubMed
15.Owens, DF, Kriegstein, AR. Developmental neurotransmitters? Neuron 2002; 36: 989–991.CrossRefGoogle ScholarPubMed
16.The Boulder Committee. Embryonic vertebrate central nervous system: revised terminology. Anat Rec 1970; 166: 257–261.CrossRefGoogle Scholar
17.Sidman, RL, Miale, IL, Feder, N. Cell proliferation and migration in the primitive ependymal zone: an autoradiographic study of histogenesis in the nervous system. Exp Neurol 1959; 1: 322–333.CrossRefGoogle ScholarPubMed
18.Altman, J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 1969; 137: 433–457.CrossRefGoogle ScholarPubMed
19.Doetsch, F, Caille, I, Lim, DA et al. . Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 1999; 97: 703–716.CrossRefGoogle ScholarPubMed
20.LoTurco, JJ, Owens, DF, Heath, MJ et al. . GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 1995; 15: 1287–1298.CrossRefGoogle ScholarPubMed
21.Antonopoulos, J, Pappas, IS, Parnavelas, JG. Activation of the GABAA receptor inhibits the proliferative effects of bFGF in cortical progenitor cells. Eur J Neurosci 1997; 9: 291–298.CrossRefGoogle ScholarPubMed
22.Behar, TN, Li, YX, Tran, HT et al. . GABA stimulates chemotaxis and chemokinesis of embryonic cortical neurons via calcium-dependent mechanisms. J Neurosci 1996; 16: 1808–1818.CrossRefGoogle ScholarPubMed
23.Behar, TN, Schaffner, AE, Scott, CA et al. . GABA receptor antagonists modulate postmitotic cell migration in slice cultures of embryonic rat cortex. Cereb Cortex 2000; 10: 899–909.CrossRefGoogle ScholarPubMed
24.Haydar, TF, Wang, F, Schwartz, ML, Rakic, P. Differential modulation of proliferation in the neocortical ventricular and subventricular zones. J Neurosci 2000; 20: 5764–5774.CrossRefGoogle ScholarPubMed
25.Kornack, DR, Rakic, P. Changes in cell-cycle kinetics during the development and evolution of primate neocortex. Proc Natl Acad Sci USA 1998; 95: 1242–1246.CrossRefGoogle ScholarPubMed
26.Liu, X, Wang, Q, Haydar, TF, Bordey, A. Nonsynaptic GABA signalling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nat Neurosci 2005; 8: 1179–1187.CrossRefGoogle ScholarPubMed
27.Behar, TN, Scott, CA, Greene, CL et al. . Glutamate acting at NMDA receptors stimulates embryonic cortical neuronal migration. J Neurosci 1999; 19: 4449–4461.CrossRefGoogle ScholarPubMed
28.Rivera, C, Voipio, J, Kaila, K. Two developmental switches in GABAergic signalling: the K+–Cl− cotransporter KCC2 and carbonic anhydrase CAVII. J Physiol 2005; 562: 27–36.CrossRefGoogle ScholarPubMed
29.Miller, M. Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons. J Neurocytol 1981; 10: 859–878.CrossRefGoogle Scholar
30.Miller, M, Peters, A. Maturation of rat visual cortex. II. A combined Golgi-electron microscope study of pyramidal neurons. J Comp Neurol 1981; 203: 555–573.CrossRefGoogle Scholar
31.McAllister, AK. Cellular and molecular mechanisms of dendrite growth. Cereb Cortex 2000; 10: 963–973.CrossRefGoogle ScholarPubMed
32.Cline, HT. Dendritic arbor development and synaptogenesis. Curr Opin Neurobiol 2001; 11: 118–126.CrossRefGoogle ScholarPubMed
33.Wong, RO, Ghosh, A. Activity-dependent regulation of dendritic growth and patterning. Nat Rev Neurosci 2002; 3: 803–812.CrossRefGoogle ScholarPubMed
34.Chen, Y, Ghosh, A. Regulation of dendritic development by neuronal activity. J Neurobiol 2005; 64: 4–10.CrossRefGoogle ScholarPubMed
35.Jan, YN, Jan, LY. The control of dendrite development. Neuron 2003; 40: 229–242.CrossRefGoogle ScholarPubMed
36.Rajan, I, Cline, HT. Glutamate receptor activity is required for normal development of tectal cell dendrites in vivo. J Neurosci 1998; 18: 7836–7846.CrossRefGoogle ScholarPubMed
37.Hensch, TK. Critical period regulation. Annu Rev Neurosci 2004; 27: 549–579.CrossRefGoogle ScholarPubMed
38.Hensch, TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci 2005; 6: 877–888.CrossRefGoogle ScholarPubMed
39.Liu, G. Local structural balance and functional interaction of excitatory and inhibitory synapses in hippocampal dendrites. Nat Neurosci 2004; 7: 373–379.CrossRefGoogle ScholarPubMed
40.Olney, JW. New insights and new issues in developmental neurotoxicology. Neurotoxicology 2002; 23: 659–668.CrossRefGoogle ScholarPubMed
41.Olney, JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 1969; 164: 719–721.CrossRefGoogle ScholarPubMed
42.Olney, JW, Sharpe, LG. Brain lesions in an infant rhesus monkey treated with monsodium glutamate. Science 1969; 166: 386–388.CrossRefGoogle Scholar
43.Ikonomidou, C, Bosch, F, Miksa, M et al. . Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283: 70–74.CrossRefGoogle ScholarPubMed
44.Asada, H, Kawamura, Y, Maruyama, K et al. . Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 1997; 94: 6496–6499.CrossRefGoogle ScholarPubMed
45.Hensch, TK, Fagiolini, M, Mataga, N et al. . Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 1998; 282: 1504–1508.CrossRefGoogle ScholarPubMed
46.Adams, SM, de Rivero Vaccari, JC, Corriveau, RA. Pronounced cell death in the absence of NMDA receptors in the developing somatosensory thalamus. J Neurosci 2004; 24: 9441–9450.CrossRefGoogle ScholarPubMed
47.Li, Y, Erzurumlu, RS, Chen, C et al. . Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of NMDAR1 knockout mice. Cell 1994; 76: 427–437.CrossRefGoogle ScholarPubMed
48.Iwasato, T, Datwani, A, Wolf, AM et al. . Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 2000; 406: 726–731.CrossRefGoogle ScholarPubMed
49.Ikonomidou, C, Bittigau, P, Ishimaru, MJ et al. . Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287: 1056–1060.CrossRefGoogle ScholarPubMed
50.Albers, GW, Goldberg, MP, Choi, DW. N-methyl-d-aspartate antagonists: ready for clinical trial in brain ischemia? Ann Neurol 1989; 25: 398–403.CrossRefGoogle ScholarPubMed
51.Bullock, R. Strategies for neuroprotection with glutamate antagonists. Extrapolating from evidence taken from the first stroke and head injury studies. Ann NY Acad Sci 1995; 765: 272–278discussion 298.CrossRefGoogle ScholarPubMed
52.Himmelseher, S, Durieux, ME. Revising a dogma: ketamine for patients with neurological injury? Anesth Analg 2005; 101: 524–534.CrossRefGoogle ScholarPubMed
53.Olney, JW, Labruyere, J, Price, MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989; 244: 1360–1362.CrossRefGoogle ScholarPubMed
54.Scallet, AC, Divine, R, Wang, C et al. . Ketamine-induced neurotoxicity in prenatal rhesus monkeys: distribution of neuronal damage. Soc Neurosci Abst 2005: 251.15.Google Scholar
55.Hayashi, H, Dikkes, P, Soriano, SG. Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain. Paediatr Anaesth 2002; 12: 770–774.CrossRefGoogle ScholarPubMed
56.Scallet, AC, Schmued, LC, Slikker, W et al. . Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol Sci 2004; 81: 364–370.CrossRefGoogle ScholarPubMed
57.Young, C, Jevtovic-Todorovic, V, Qin, YQ et al. . Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005; 146: 189–197.CrossRefGoogle ScholarPubMed
58.Webb, SJ, Monk, CS, Nelson, CA. Mechanisms of postnatal neurobiological development: implications for human development. Dev Neuropsychol 2001; 19: 147–171.CrossRefGoogle ScholarPubMed
59.Gascon, E, Vutskits, L, Zhang, H et al. . Sequential activation of p75 and TrkB is involved in dendritic development of subventricular zone-derived neuronal progenitors in vitro. Eur J Neurosci 2005; 21: 69–80.CrossRefGoogle ScholarPubMed
60.Malinovsky, JM, Servin, F, Cozian, A et al. . Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 1996; 77: 203–207.CrossRefGoogle ScholarPubMed
61.Weber, F, Wulf, H, Gruber, M, Biallas, R. S-ketamine and S-norketamine plasma concentrations after nasal and i.v. administration in anesthetized children. Paediatr Anaesth 2004; 14: 983–988.CrossRefGoogle ScholarPubMed
62. Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Effect of ketamine on dendritic arbor development and survival of immature GABAergic neurons in vitro. Toxicol Sci 2006; e-pub ahead.CrossRefGoogle Scholar
63.Adams, HA. Mechanisms of action of ketamine. Anaesthesiol Reanim 1998; 23: 60–63.Google ScholarPubMed
64.Kari, HP, Davidson, PP, Kohl, HH, Kochhar, MM. Effects of ketamine on brain monoamine levels in rats. Res Commun Chem Pathol Pharmacol 1978; 20: 475–488.Google ScholarPubMed
65.Tso, MM, Blatchford, KL, Callado, LF et al. . Stereoselective effects of ketamine on dopamine, serotonin and noradrenaline release and uptake in rat brain slices. Neurochem Int 2004; 44: 1–7.CrossRefGoogle ScholarPubMed
66.Nishimura, M, Sato, K, Okada, T et al. . Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology 1998; 88: 768–774.CrossRefGoogle ScholarPubMed
67.Bozzi, Y, Borrelli, E. Dopamine in neurotoxicity and neuroprotection: what do D(2) receptors have to do with it? Trends Neurosci 2006; 29: 167–174.CrossRefGoogle Scholar
68.McKittrick, CR, Magarinos, AM, Blanchard, DC et al. . Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding to serotonin transporter sites. Synapse 2000; 36: 85–94.3.0.CO;2-Y>CrossRefGoogle ScholarPubMed
69.Mazar, J, Rogachev, B, Shaked, G et al. . Involvement of adenosine in the antiinflammatory action of ketamine. Anesthesiology 2005; 102: 1174–1181.CrossRefGoogle ScholarPubMed
70.Tebano, MT, Martire, A, Rebola, N et al. . Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: a possible key mechanism in the modulation of N-methyl-d-aspartate effects. J Neurochem 2005; 95: 1188–1200.CrossRefGoogle ScholarPubMed
71.Keilhoff, G, Bernstein, HG, Becker, A et al. . Increased neurogenesis in a rat ketamine model of schizophrenia. Biol Psychiatry 2004; 56: 317–322.CrossRefGoogle Scholar
72.Bjönström, K, Sjölander, A, Schippert, A, Eintrei, C. A tyrosine kinase regulates propofol-induced modulation of the β-subunit of the GABAA receptor and release of intracellular calcium in cortical rat neurons. Acta Physiol Scand 2002; 175: 227–235.CrossRefGoogle Scholar
73.Wooltorton, E. Propofol contraindicated for sedation of pediatric intensive care patients. CMAJ 2002; 167: 507.Google ScholarPubMed
74.Crawford, MW, Dodgson, BG, Holtby, HH, Roy, WL. Propofol syndrome in children. CMAJ 2003; 168: 669author reply 669–70.Google ScholarPubMed
75.Westrin, P. The induction dose of propofol in infants 1–6 months of age and in children 10–16 years of age. Anesthesiology 1991; 74: 455–458.CrossRefGoogle ScholarPubMed
76.Murat, I, Billard, V, Vernois, J et al. . Pharmacokinetics of propofol after a single dose in children aged 1–3 years with minor burns. Comparison of three data analysis approaches. Anesthesiology 1996; 84: 526–532.CrossRefGoogle ScholarPubMed
77.Honegger, P, Matthieu, JM. Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures. J Neurosci Res 1996; 45: 631–636.3.0.CO;2-1>CrossRefGoogle ScholarPubMed
78.Spahr-Schopfer, I, Vutskits, L, Toni, N et al. . Differential neurotoxic effects of propofol on dissociated cortical cells and organotypic hippocampal cultures. Anesthesiology 2000; 92: 1408–1417.CrossRefGoogle ScholarPubMed
79.Vutskits, L, Gascon, E, Tassonyi, E, Kiss, JZ. Clinically relevant concentrations of propofol but not midazolam alter in vitro dendritic development of isolated gamma-aminobutyric acid-positive interneurons. Anesthesiology 2005; 102: 970–976.CrossRefGoogle Scholar
80.Arcangeli, A, Antonelli, M, Mignani, V, Sandroni, C. Sedation in PACU: the role of benzodiazepines. Curr Drug Targets 2005; 6: 745–748.CrossRefGoogle ScholarPubMed
81.Mohler, H, Fritschy, JM, Vogt, K et al. . Pathophysiology and pharmacology of GABAA receptors. Handb Exp Pharmacol 2005; 169: 225–247.CrossRefGoogle Scholar
82.Stephenson, FA, Duggan, MJ, Pollard, S. The gamma 2 subunit is an integral component of the gamma-aminobutyric acidA receptor but the alpha 1 polypeptide is the principal site of the agonist benzodiazepine photoaffinity labeling reaction. J Biol Chem 1990; 265: 21160–21165.CrossRefGoogle ScholarPubMed
83.Orser, BA, Bertlik, M, Wang, LY, MacDonald, JF. Inhibition by propofol (2,6 diisopropylphenol) of the N-methyl-d-aspartate subtype of glutamate receptor in cultured hippocampal neurones. Br J Pharmacol 1995; 116: 1761–1768.CrossRefGoogle ScholarPubMed
84.Flood, P, Ramirez-Latorre, J, Role, L. Alpha 4 beta 2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology 1997; 86: 859–865.CrossRefGoogle ScholarPubMed
85.Todorovic, SM, Lingle, CJ. Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents. J Neurophysiol 1998; 79: 240–252.CrossRefGoogle ScholarPubMed
86.Oscarsson, A, Massoumi, R, Sjolander, A, Eintrei, C. Reorganization of actin in neurons after propofol exposure. Acta Anaesthesiol Scand 2001; 45: 1215–1220.CrossRefGoogle ScholarPubMed
87.Bjornstrom, K, Eintrei, C. The difference between sleep and anaesthesia is in the intracellular signal: propofol and GABA use different subtypes of the GABAA receptor beta subunit and vary in their interaction with actin. Acta Anaesthesiol Scand 2003; 47: 157–164.CrossRefGoogle ScholarPubMed
88.Uemura, E, Bowman, RE. Effects of halothane on cerebral synaptic density. Exp Neurol 1980; 69: 135–142.CrossRefGoogle ScholarPubMed
89.Uemura, E, Levin, ED, Bowman, RE. Effects of halothane on synaptogenesis and learning behavior in rats. Exp Neurol 1985; 89: 520–529.CrossRefGoogle ScholarPubMed
90.Levin, ED, Uemura, E, Bowman, RE. Neurobehavioral toxicology of halothane in rats. Neurotoxicol Teratol 1991; 13: 461–470.CrossRefGoogle ScholarPubMed
91.Wise-Faberowski, L, Zhang, H, Ing, R et al. . Isoflurane-induced neuronal degeneration: an evaluation in organotypic hippocampal slice cultures. Anesth Analg 2005; 101: 651–657.CrossRefGoogle ScholarPubMed
92.Stratmann, G, Bickler, P, Ku, B et al. . Isoflurane increases stem cell proliferation in adult but not in rat neonatal hippocampi. Soc Neurosci Abst 2005; 826–829.Google Scholar
93.Mullenix, PJ, Moore, PA, Tassinari, MS. Behavioral toxicity of nitrous oxide in rats following prenatal exposure. Toxicol Ind Health 1986; 2: 273–287.CrossRefGoogle ScholarPubMed
94.Jevtovic-Todorovic, V, Benshoff, N, Olney, JW. Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol 2000; 130: 1692–1698.CrossRefGoogle ScholarPubMed
95.Jevtovic-Todorovic, V, Hartman, RE, Izumi, Y et al. . Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23: 876–882.CrossRefGoogle ScholarPubMed
96. Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V. General anesthesia activates BDNF-dependent neuroapotosis in the developing brain. Apoptosis 2006; May30 (Epub ahead of print).CrossRefGoogle Scholar
97.Tenq, KK, Hempstead, BL. Neurotrophins and their receptors: signaling trios in complex biological systems. Cell Mol Life Sci 2004; 61: 35–48.CrossRefGoogle Scholar
98.Yon, JH, Carter, LB, Reiter, RJ, Jevtovic-Todorovic, V. Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis 2006; 21: 522–530.CrossRefGoogle ScholarPubMed
99.Berde, C, Cairns, B. Developmental pharmacology across species: promise and problems. Anesth Analg 2000; 91: 1–5.CrossRefGoogle Scholar
100.Rizzi, S, Carter, LB, Jevtovic-Todorovic, V. Clinically used general anesthetics induce neuroapoptosis in the developing piglet brain. Soc Neurosci Abst 2005; 251.7.Google Scholar
101.Anand, KJ, Soriano, SG. Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 2004; 101: 527–530.CrossRefGoogle ScholarPubMed
102.Clancy, B, Darlington, RB, Finlay, BL. Translating developmental time across mammalian species. Neuroscience 2001; 105: 7–17.CrossRefGoogle ScholarPubMed
103.Roytblat, L, Talmor, D, Rachinsky, M et al. . Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998; 87: 266–271.CrossRefGoogle ScholarPubMed
104.Zilberstein, G, Levy, R, Rachinsky, M et al. . Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth Analg 2002; 95: 531–536.CrossRefGoogle ScholarPubMed
105.Lipton, SA, Nakanishi, N. Shakespeare in love – with NMDA receptors? Nat Med 1999; 5: 270–271.CrossRefGoogle ScholarPubMed
106.Bhutta, AT, Anand, KJ. Vulnerability of the developing brain. Neuronal mechanisms. Clin Perinatol 2002; 29: 357–372.CrossRefGoogle ScholarPubMed
107.Olney, JW, Young, C, Wozniak, DF et al. . Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology 2004; 101: 273–275.CrossRefGoogle ScholarPubMed
108.Dobbing, J. Undernutrition and the developing brain. The relevance of animal models to the human problem. Am J Dis Child 1970; 120: 411–415.CrossRefGoogle Scholar
109.Lucas, A, Morley, R, Cole, TJ. Randomised trial of early diet in preterm babies and later intelligence quotient. BMJ 1998; 317: 1481–1487.CrossRefGoogle ScholarPubMed
110.Todd, MM. Anesthetic neurotoxicity: the collision between laboratory neuroscience and clinical medicine. Anesthesiology 2004; 101: 272–273.CrossRefGoogle ScholarPubMed
111. AHRQ:HCUPnet: Healthcare Cost and Utilization Project, Rockville, MD, Agency for Healthcare Research and Quality, 2001 (www.ahrq.gov/hcupnet).Google Scholar
112.Cohen, MM, Cameron, CB, Duncan, PG. Pediatric anesthesia morbidity and mortality in the perioperative period. Anesth Analg 1990; 70: 160–167.CrossRefGoogle ScholarPubMed
113.Anand, KJ, Aranda, JV, Berde, CB et al. . Analgesia and anesthesia for neonates: study design and ethical issues. Clin Ther 2005; 27: 814–843.CrossRefGoogle ScholarPubMed