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Year : 2013  |  Volume : 57  |  Issue : 3  |  Page : 221-222  

Safety first, safety at early age: The quagmire of neurotoxicity in paediatric anaesthesia

Department of Anaesthesiology and Critical Care, Vijayanagar Institute of Medical Sciences, Bellary, Karnataka, India

Date of Web Publication25-Jul-2013

Correspondence Address:
S Bala Bhaskar
Department of Anaesthesiology and Critical Care, Vijayanagar Institute of Medical Sciences, Bellary, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-5049.115572

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How to cite this article:
Bhaskar S B. Safety first, safety at early age: The quagmire of neurotoxicity in paediatric anaesthesia. Indian J Anaesth 2013;57:221-2

How to cite this URL:
Bhaskar S B. Safety first, safety at early age: The quagmire of neurotoxicity in paediatric anaesthesia. Indian J Anaesth [serial online] 2013 [cited 2020 Sep 19];57:221-2. Available from: http://www.ijaweb.org/text.asp?2013/57/3/221/115572

Millions of surgeries and procedures are performed world-wide in children and sedatives and anaesthetic agents have sometimes been used with impunity in these cases. The modern anaesthetic agents have good safety profiles as far as the immediate goals of anaesthesia and post-operative period are concerned. Increasingly, concerns have cropped up on their long-term adverse effects on the neural structure and neurocognitive function, more so in neonates and infants. Much of the evidence is based on animal studies (preclinical) and few retrospective human clinical studies; human prospective clinical studies are few.

What is known is that the anaesthetics exert their effects by action on multiple receptors and ion channels in the central nervous system. Intravenous agents are more potent than the inhalational agents but have similar effects on the various receptors and channels involved in anaesthesia. It is also known that anaesthetics induce neuroapoptosis, an active programmed cell death. [1] It could involve promotion of the physiological apoptosis or induction of pathological apoptosis. Spurt in brain growth or synaptogenesis occurs in early postnatal period in the majority of experimental animals and in humans, it starts in mid- gestation and extends for few years into childhood. The risk of damage to neuronal tissue is therefore, maximum during this period. Inhibitions of brain-derived neurotrophic factor (BDNF) signalling pathways by agents with N-methyl-D-aspartate glutamate (NMDA) receptor antagonism, or γ-amino-butyric acid (GABA) type. Receptor agonism or both (ethanol) are associated with extensive neuronal apoptosis in animal models. [1],[2] BDNF is essential for growth, differentiation and survival of neuronal tissue. Other proposed neural effects of these agents include alteration in dendritic spine architecture. [3]

Simultaneous with the evidence of harmful effects of anaesthetics in preclinical studies, it has also been found that neurodegeneration and apoptosis are prevented/countered by agents such as lithium, dexmedetomidine and xenon. [4],[5],[6],[7],[8] Dexmedetomidine and xenon are known to reduce isoflurane induced neuronal apoptosis in neonatal rats. [6],[7],[8] Xenon was found to retain its apoptotic effects while diminishing isoflurane-induced cellular death. [8]

Studies since 1980's, in vitro and in vivo, have shown conflicting effects of anaesthetic and sedative agents in experimental animals. Benzodiazepines, nitrous oxide, halothane, enflurane, isoflurane, sevoflurane, propofol, ketamine and others have been studied, some possibly precipitating and some reducing neuronal degeneration. [1] The dose of the agent, duration of exposure and use of multiple agents may all increase the risk. [9] Propofol used in subanaesthetic doses has been shown to induce neuronal apoptosis. [10] Midazolam, nitrous oxide, isoflurane combination is used commonly in paediatric anaesthesia; these drugs have been found to promote BDNF activated neuroapoptosis in rats. [1],[10],[11]

Retrospective studies in humans indicated that learning disability was likely with multiple postnatal anaesthetic exposures at an early age. [12] The results and correlations of some older studies need not influence the current practice as halothane is almost phased out in the majority of countries and use of nitrous oxide has also become less frequent. The criteria used to describe learning disability in such studies may not reflect specific neuronal injury and to extrapolate the results of animal studies to humans may not be the optimum approach. Structurally, the threshold for apoptotic changes leading to actual injury may be higher in humans as compared to animals. The animal models used in studies were subject to various drugs and largely disregarded the noxious stimuli, obtained during surgeries in humans. No confounding conditions such as sepsis, hypoglycaemia, hypotension, stress of anaesthesia and surgery and other critical states existed in animal models, which otherwise could contribute to or precipitate neuronal changes in humans under anaesthesia/sedation.

Large, prospective, human multicentric studies are underway in paediatric patients undergoing hernia surgeries, a common surgery in the paediatric population. Paediatric anaesthesia and neurodevelopment assessment (PANDA) project is designed to compare children exposed to general anaesthesia (before 36 months of age) with their siblings who are not, with regard to neurodevelopment and cognitive functions between 8 and 15 years of age. [13] General anaesthesia spinal (GAS) study is another on-going randomized controlled trial, aimed to investigate the long-term effects of spinal and general anaesthesia in new-born and tested for developmental outcomes at 2 years of age and neurodevelopmental and intelligence outcomes at 5 years. If similar scores are obtained in two groups, the preclinical evidences may need to be revisited and future studies redesigned. Similarly, Mayo Safety in Kids (MASK) Study is a population-based cohort study of long-term cognitive development in children with no anaesthetic exposure to those with single or multiple exposures before 3 years of age.

As human studies are difficult to conduct and interpret, it is better to be careful in managing anaesthesia in younger patients, at least until 4 years of age, based on the present retrospective human data. Prolonged exposure to sedatives and anaesthetic agents or use of multiple drugs should be avoided. Advances in anaesthetic pharmacology and monitoring have allowed complicated surgeries to be conducted safely in paediatric patients. The benefit of surgery must be weighed with the potential for neuronal and behavioural adverse effects of the anaesthetic agents. Current safe practices of modern anaesthesia however should not be the casualty till sound evidence emerges, necessitating specific recommendations for or against the use of agents.

   References Top

1.Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V. General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 2006;11:1603-15.  Back to cited text no. 1
2.Fredriksson A, Pontén E, Gordh T, Eriksson P. Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007;107:427-36.  Back to cited text no. 2
3.Briner A, De Roo M, Dayer A, Muller D, Habre W, Vutskits L. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology 2010;112:546-56.  Back to cited text no. 3
4.Straiko MM, Young C, Cattano D, Creeley CE, Wang H, Smith DJ, et al. Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology 2009;110:862-8.  Back to cited text no. 4
5.Young C, Straiko MM, Johnson SA, Creeley C, Olney JW. Ethanol causes and lithium prevents neuroapoptosis and suppression of pERK in the infant mouse brain. Neurobiol Dis 2008;31:355-60.  Back to cited text no. 5
6.Sanders RD, Xu J, Shu Y, Januszewski A, Halder S, Fidalgo A, et al. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 2009;110:1077-85.  Back to cited text no. 6
7.Ma D, Williamson P, Januszewski A, Nogaro MC, Hossain M, Ong LP, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology 2007;106:746-53.  Back to cited text no. 7
8.Cattano D, Williamson P, Fukui K, Avidan M, Evers AS, Olney JW, et al. Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain. Can J Anaesth 2008;55:429-36.  Back to cited text no. 8
9.Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005;146:189-97.  Back to cited text no. 9
10.Cattano D, Young C, Straiko MM, Olney JW. Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008;106:1712-4.  Back to cited text no. 10
11.Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82.  Back to cited text no. 11
12.Wilder RT, Flick RP, Sprung J, 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.  Back to cited text no. 12
13.Pediatric Anesthesia and Neurodevelopment Assessment (PANDA), Available from: http://www.kidspandastudy.org/index.html [Last accessed on 2013 May 7].  Back to cited text no. 13

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