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Liaisons dangereuses? General anaesthetics and long-term toxicity in the CNS

Published online by Cambridge University Press:  08 August 2006

M. Perouansky
M. Perouansky
Affiliation:
University of Wisconsin, Department of Anesthesiology, Madison, WI, USA
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Abstract

Summary

We do not know how general anaesthetics cause their desired effects. Contrary to what has been thought until relatively recently, the clinical state of anaesthesia consists of multiple components that are mediated via interaction of the anaesthetic drugs with different targets on the molecular, the cellular, the network and the structural–anatomical levels. The mechanisms by which some of these drugs induce the different components of ‘anaesthesia’ may be rather specific: discrete mutations of single amino acids in specific proteins profoundly affect the ability of certain anaesthetics to achieve specific endpoints. Despite this potential specificity, inhalational anaesthetics are present in the body at very high concentrations during surgical anaesthesia. Due to their lipid solubility, general anaesthetics dissolve in every membrane, penetrate into organelles and interact with numerous cellular structures in multiple ways. A priori, it is therefore not unreasonable to assume that these drugs have the potential to cause insidious changes in the body other than those acute and readily apparent ones that we routinely monitor for. Some changes may wane within a short time after removal of the drug (e.g. the suppression of immune cell function). Others may persist after complete removal of the drug and even become self-propagating (e.g. spread of malignant cells, the β-oligomerization of proteins), still others may be irreversible (e.g. the induction of apoptosis in the central nervous system) but of unclear significance. This article will focus on evidence for anaesthetic toxicity in the central nervous system, which appears to be susceptible to anaesthetic neurotoxicity primarily at the extremes of ages but via different pathways: in the neonate, during the period of most intense synaptogenesis, anaesthetics can induce excessive apoptosis; in the aging brain subtle cognitive dysfunction can persist long after clearance of the drug and processes resembling neurodegenerative disorders may be accelerated. At all ages, anaesthetics affect gene expression regulating protein synthesis in poorly understood ways. While it seems reasonable to assume that the vast majority of our patients completely restore homeostasis after general anaesthesia, exposure to these drugs probably has more profound and longer-lasting effects on the brain than heretofore imagined.

Keywords

ANAESTHETICS INHALATIONALANAESTHETICS INTRAVENOUSCENTRAL NERVOUS SYSTEM, adverse effects, toxicityNEONATE
Type
Review
Information
European Journal of Anaesthesiology , Volume 24 , Issue 2 , February 2007 , pp. 107 - 115
Copyright
2007 European Society of Anaesthesiology

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References

Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated ‘menage a trois’. Trend Neurosci 1997; 20 (11): 523–529.Google Scholar
Marota JJ, Crosby G, Uhl GR. Selective effects of pentobarbital and halothane on c-fos and jun-B gene expression in rat brain. Anesthesiology 1992; 77 (2): 365–371.Google Scholar
Takayama K, Suzuki T, Miura M. The comparison of effects of various anesthetics on expression of fos protein in the rat-brain. Neurosci Lett 1994; 176 (1): 59–62.Google Scholar
Hamaya Y, Takeda T, Dohi S, Nakashima S, Nozawa Y. The effects of pentobarbital, isoflurane, and propofol on immediate-early gene expression in the vital organs of the rat. Anesth Analg 2000; 90 (5): 1177–1183.Google Scholar
Culley DJ, Yukhananov RY, Crosby G. Hippocampal gene expression is altered 48 hours after general anesthesia in aged rats. Anesthesiology 2004; 101: A64.Google Scholar
Atkins JH, Johansson JS. Technologies to shape the future: proteomics applications in anesthesiology and critical care medicine. Anesth Analg 2006; 102 (4): 1207–1216.Google Scholar
Futterer CD, Maurer MH, Schmitt A, Feldmann RE, Kuschinsky W, Waschke KF. Alterations in rat brain proteins after desflurane anesthesia. Anesthesiology 2004; 100 (2): 302–308.Google Scholar
Kalenka A, Maurer MH, Feldmann RE, Kuschinsky W, Waschke KF. Volatile anesthetics evoke prolonged changes in the proteome of the left ventricule myocardium: defining a molecular basis of cardioprotection? Acta Anaesthesiol Scand 2006; 50 (4): 414–427.Google Scholar
Xiong L, Zheng Y, Wu M, Hou L, Zhu Z, Zhang Xet al. Preconditioning with isoflurane produces dose-dependent neuroprotection via activation of adenosine triphosphate-regulated potassium channels after focal cerebral ischemia in rats. Anesth Analg 2003; 96 (1): 233–237.Google Scholar
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002; 297 (5580): 353–356.Google Scholar
Walsh DM, Selkoe DJ. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 2004; 44 (1): 181–193.Google Scholar
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MSet al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416 (6880): 535–539.Google Scholar
Eckenhoff RG, Johansson JS, Wei HF, Carnini A, Kang BB, Wei WLet al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology 2004; 101 (3): 703–709.Google Scholar
Wei H, Liang G, Wei W, Li Y, Eckenhoff RG. Volatile anesthetics induce neurotoxicity differently in PC12 cells featured with Alzheimer's Disease. Anesthesiology 2005; 103: A121.Google Scholar
Mikkelsen H, Rentowl P, Rasmussen LS, Hanning CD, Moller JT. Cognitive dysfunction may persist 1–2 years after major non-cardiac surgery. Anesthesiology 1998; 89 (3A): U963.Google Scholar
Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet Jet al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998; 351 (9106): 857–861.Google Scholar
Rasmussen LS, Johnson T, Kuipers HM, Kristensen D, Siersma VD, Vila Pet al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients. Acta Anaesth Scand 2003; 47 (3): 260–266.Google Scholar
Komatsu H, Nogaya J, Anabuki D, Yokono S, Kinoshita H, Shirakawa Yet al. Memory facilitation by posttraining exposure to halothane, enflurane, and isoflurane in ddN mice. Anesth Analg 1993; 76 (3): 609–612.Google Scholar
Culley DJ, Baxter M, Yukhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg 2003; 96 (4): 1004–1009.Google Scholar
Crosby C, Culley DJ, Baxter MG, Yukhananov R, Crosby G. Spatial memory performance 2 weeks after general anesthesia in adult rats. Anesth Analg 2005; 101 (5): 1389–1392.Google Scholar
Culley DJ, Baxter MG, Crosby CA, Yukhananov R, Crosby G. Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane–nitrous oxide anesthesia in aged rats. Anesth Analg 2004; 99 (5): 1393–1397.Google Scholar
Miro O, Barrientos A, Alonso JR, Casademont J, Jarreta D, Urbano-Marquez Aet al. Effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle. Eur J Clin Pharmacol 1999; 55 (1): 35–41.Google Scholar
Kayser EB, Morgan PG, Sedensky MM. GAS-1: a mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans. Anesthesiology 1999; 90 (2): 545–554.Google Scholar
Morgan PG, Hoppel CL, Sedensky MM. Mitochondrial defects and anesthetic sensitivity. Anesthesiology 2002; 96 (5): 1268–1270.Google Scholar
Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J, Dikranian Ket al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999; 283 (5398): 70–74.Google Scholar
Mennerick S, Zorumski CF. Neural activity and survival in the developing nervous system. Mol Neurobiol 2000; 22 (1–3): 41–54.Google Scholar
Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz Ket al. Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287 (5455): 1056–1060.Google Scholar
Kumada T, Lakshmana MK, Komuro H. Reversal of neuronal migration in a mouse model of fetal alcohol syndrome by controlling second-messenger signalings. J Neurosci 2006; 26 (3): 742–756.Google Scholar
Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CFet al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003; 23 (3): 876–882.Google Scholar
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 (3): 815–827.Google Scholar
Anand KJ, Soriano SG. Anesthetic agents and the immature brain: are these toxic or therapeutic? Anesthesiology 2004; 101 (2): 527–530.Google Scholar
Loepke AW, McCann JC, Kurth D, McAuliffe JJ. The physiologic effects of isoflurane anesthesia in neonatal mice. Anesth Analg 2006; 102: 75–80.Google Scholar
Auer RN. Hypoglycemic brain damage. Metab Brain Dis 2004; 19 (3–4): 169–175.Google Scholar
Belik J, Wagerle LC, Stanley CA, Sacks LM, Herbert DW, Delivoriapapadopoulos M. Cerebral metabolic response and mitochondrial activity following insulin-induced hypoglycemia in newborn lambs. Biol Neonate 1989; 55 (4–5): 281–289.Google Scholar
Rizzi S, Yon JH, Carter LB, Jevtovic-Todorovic V. Short exposure to general anesthesia caused widespread neuronal suicide in the developing guinea pig brain. Soc Neurosci Program 2005; 241: 6.Google Scholar
Wise-Faberowski L, Zhang H, Ing R, Pearlstein RD, Warner DS. Isoflurane-induced neuronal degeneration: an evaluation in organotypic hippocampal slice cultures. Anesth Analg 2005; 101 (3): 651–657 (Table).Google Scholar
Olney JW, Young C, Wozniak DF, Ikonomidou C, Jevtovic-Todorovic V. Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology 2004; 101 (2): 273–275.Google Scholar
Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere Jet al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Brit J Pharmacol 2005; 146 (2): 189–197.Google Scholar
Rizzi S, Carter LB, Jevtovic-Todorovic V. Clinically used general anesthetics induce neuroapoptosis in the developing piglet brain. Soc Neurosci Prog 2005; 251: 7.Google Scholar
Culley DJ, Baxter MG, Yukhananov R, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane–nitrous oxide anesthesia in rats. Anesthesiology 2004; 100 (2): 309–314.Google Scholar
Houx PJ, Vreeling FW, Jolles J. Age-associated cognitive decline is related to biological life events. In: Iqbal K, McLachlan DRC, Winblad B, Wisniewski HS, eds. Alzheimer's Disease: Basic Mechanisms, Diagnosis, and Therapeutic Strategies.Chichester, UK: John Wiley & Sons, 1991: 353–358.