The exposure of infants and children to surgery and general anaesthesia has dramatically increased in recent decades. A report from the USA National Center for Health Statistics estimated that 6 million children undergo surgical care each year in the United States.1 The widespread use of general anaesthetics in paediatric anaesthesia makes its well tolerated application an extremely important issue in public health. In 1999, John Olney and colleagues first reported that N-methyl-d-aspartate (NMDA) antagonists, including ketamine, triggered widespread neuroapoptosis in the developing brain.2 Subsequently, researchers could show that many anaesthetics, including nitrous oxide, isoflurane and ketamine, induced apoptotic changes in the brain of neonatal rodents.3 More importantly, several general anaesthetics were proved to induce long-term cognitive impairment in different animal models.4–6 There were, however, some studies displaying potentially protective effects of general anaesthetics on the developing brain.7,8 As a result, a growing number of studies addressed the effects of inhalational anaesthetics on the immature brain in recent years (Supplementary Digital Content Tables 1 and 2, http://links.lww.com/EJA/A47). We provide an overview of the available preclinical evidence gained in the past 5 years on both the detrimental effects and the neuroprotective potential in special settings, of inhaled anaesthetics on the developing brain.
Materials and methods
A PubMed search was performed in June 2013 with the following keywords: published in the last 5 years, animals, (inhaled anesthesia OR inhaled anaesthesia OR inhaled anesthetic OR inhaled anaesthetic OR inhaled narcotic OR inhalational anesthesia OR inhalational anaesthesia OR inhalational anesthetic OR inhalational anaesthetic OR inhalational narcotic OR volatile anesthetic OR volatile anaesthetic) AND (neuro* OR brain OR cerebral OR apoptosis OR toxicity OR impairment OR disability OR disorder OR abnormal OR deficit OR injury OR insult OR protect*) AND (pediatric OR child* OR baby OR infant OR newborn OR neonat* OR developing OR immature OR fetus OR fetal OR embryo OR young). The reference lists of relevant articles and recent reviews were also hand-searched for additional studies.
The search strategy revealed 196 relevant titles. An additional 23 titles were discovered by a hand-search of the reference lists of relevant articles and recent reviews. In total, 216 records were identified after duplicates have been removed. Only 81 studies, however, studies were included in this systematic review. One hundred and thirty-five records were excluded due to the following reasons: review articles (26 studies); comments (two studies); studies in which the animals have completed their biological development (16 studies); studies that discussed the effects of agents except for inhaled anaesthetics (17 studies); studies that concerned the changes outside the central nervous system (39 studies); and studies that focused on the issues other than the detrimental or the neuroprotective effects of inhaled anaesthetics (35 studies). The procedures and results of the literature search are summarised in Fig. 1.
Sixty-eight articles assessed the structural and/or functional abnormalities induced by inhaled anaesthetics in the developing brain, and the possible protective approaches (Supplementary Digital Content Table 1, http://links.lww.com/EJA/A47). Isoflurane was the anaesthetic agent addressed most frequently (in 30 studies), and sevoflurane was the second (16 studies). Three studies dealt with xenon, and one study involved nitrous oxide. Ten studies used anaesthetic cocktails (e.g. isoflurane and nitrous oxide, or a further combination with midazolam) in the experiments. A further eight studies compared the efficiency of two or more anaesthetics. Referring to the animal species, 63 of the studies were carried out in rodents, two were in piglets and three were in primates. Twenty-six of the articles reported long-term neurobehavioural dysfunction in animals. In contrast, 13 articles focused on the protective profile of inhalational anaesthetics on perinatal hypoxic-ischaemic brain injury (Supplementary Digital Content Table 2, http://links.lww.com/EJA/A47). Seven of them dealt with the effect of noble gases, and six focused on volatile anaesthetics. Among these studies, 11 were carried out in rodents, and the remaining two were in piglets. Eight of the articles confirmed the protective effect of inhaled anaesthetics with neurobehavioural tests.
Several studies reported developmental neurotoxicity of inhaled anaesthetic agents in rodents, piglets and primates. Apoptotic neuronal death, influence on neurogenesis, impacts on synaptogenesis and axon guidance, glial cell impairment, neuroinflammation, cytosolic Ca2+ increase and mitochondrial dysfunction were identified as possible mechanisms of inhaled anaesthetic-induced toxicity in the immature brain. Administration of xenon, dexmedetomidine, hydrogen, pramipexole (PPX), EUK-134, N-stearoyl-l-tyrosine (NsTyr), bumetanide, recombinant erythropoietin (rEPO) and environmental enrichment exerted therapeutic effect. On the contrary, volatile anaesthetics may be advantageous when used for a defined period in perinatal hypoxic-ischaemic brain injury. In addition, the noble gases such as xenon and argon, were demonstrated to be effective neuroprotectants in models of perinatal hypoxic-ischaemic brain injury.
Our review has highlighted a considerable number of preclinical studies showing that the immature brain is vulnerable to inhaled anaesthetic agents. In contrast, in perinatal hypoxic-ischaemic brain injury models, inhalational anaesthetics exerted neuroprotective effects including both pre- and postconditioning mechanisms.
Detrimental effects of inhaled anaesthetics on the developing brain in rodents, piglets and primates
Both in-vivo and in-vitro exposure of gestational and neonatal rodents to inhaled anaesthetics lead to neurotoxicity in the developing brain. Only a few studies, however, studies could identify cognitive impairment persisting into juvenile or adulthood. In addition, immature piglets and primates seem to be vulnerable to inhalational anaesthesia exposure. However, unlike primates and rodents, cognition has not been assessed in pigs (Supplementary Digital Content Table 1, http://links.lww.com/EJA/A47).
There are various theories attempting to explain the mechanism of inhalational anaesthetic-induced toxicity in the immature brain. Inhaled anaesthetic agents displayed neurodegenerative effects by inducing apoptotic neuronal death in specific brain regions.9–14 The cortex, hippocampus, thalamus and basal ganglia appear particularly sensitive to anaesthetics.9,12,13 Some researchers considered the influence of anaesthetics on neurogenesis as another important mechanism.15–17 Neurogenesis occurs during brain development and persists in the subventricular zone and the hippocampal dentate gyrus in the adult brain, in which it is important for certain types of learning and memory.16 It was shown that exposure of neonatal rodents to inhaled anaesthetics resulted in reduction of neurogenesis, and subsequently lead to progressive and persistent cognitive deficits.15,16 In order to maintain the normal function of the brain, the central nervous system requires proper formation of precise neuronal circuits during brain maturation. External factors that affect synaptogenesis and axon guidance may interfere with neuronal network development, thus leading to dysfunction of the brain later in life.18 Inhalational anaesthetic agents impacted upon synaptogenesis by disturbing actin cytoskeletal depolymerisation sculpting and altering dendritic spine architecture.11,18–20 Axon guidance is a process that is vital to circuit formation and normal brain development, as axons are required to navigate over long distances to form synapses with appropriate dendritic targets. A range of severe cognitive defects are features of human developmental disorders that result from disrupted axon guidance.21,22 Mintz et al.22,23 determined that inhaled anaesthetics disturbed axon guidance by acting via γ-aminobutyric acid (GABA)-mediated mechanisms, and thus potentially interfered with circuit formation. Inhalational anaesthetics not only influence the survival and development of neurons but also impact on glial cells. Brambrink et al.24 demonstrated in the rhesus macaque that isoflurane-induced apoptosis involved both white matter and grey matter with selectively vulnerable oligodendrocytes. Lunardi et al.19 showed that exposure to isoflurane impaired the growth of immature astrocytes and morphological development. In addition, neuroinflammation, including microglia activation and increase of proinflammatory cytokines in the brain, may result in cognitive disorder.25,26 It was shown that exposure of neonatal mice to sevoflurane induced neuroinflammation and cognitive impairment; the latter was ameliorated by anti-inflammatory treatment.27 Inhaled anaesthetic agents were thought to increase cytosolic Ca2+ via activation of GABAA receptor, one of the main receptors responsible for the anaesthesia effect of general anaesthetics, thereby influencing neuronal plasticity and exerting a deleterious effect in the developing brain.28,29 Furthermore, Sanchez et al.30 and Boscolo et al.31,32 found in their experiments that inhalational anaesthetics impaired mitochondrial morphogenesis and synaptic transmission, caused mitochondrial dysfunction, extensive reactive oxygen species (ROS) upregulation and lipid peroxidation in neonatal rat subiculum, and induced long-term cognitive impairment later in life.
Exposure time is crucial for subsequent outcomes of anaesthetic-induced neurotoxicity. The brain is especially vulnerable during early development. For example, neither single nor multiple exposures of the adult mice or rats to inhaled anaesthetics lead to detrimental effect on the brain, whereas the same anaesthesia regimens administrated to neonatal rodents resulted in significant histopathology and neurocognitive impairments.15,16,27 Interestingly, the immature brain seems to be less effected by anaesthetic-induced toxicity as animals grow older. In one study, exposure of 1-month-old mice to isoflurane resulted only in a transient decrease of filopodial (small membranous protrusions found primarily on dendritic stretches of developing neurons) elimination, which disappeared within 1 day after the animals awakened.33 It is worth noting, however, that in the experiment carried out by Hofacer et al.,34 anaesthetic-induced neuroapoptosis was shown to extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb, although the absolute number of dying cells was much less than in young mice. As the authors pointed out, this finding suggested that anaesthetic vulnerability did not reflect the age of the organism, but the age of the neuron, and therefore may potentially not only be relevant to children but also to adults undergoing anaesthesia.34
As many inhaled anaesthetics have been demonstrated to cause neuroapoptosis and persistent learning deficits when given to young animals, comparison of agent-specific differences in the development of neurotoxicity is of great interest in order to minimise the adverse outcomes after anaesthetic exposure to the immature brain. Some studies compared the neuroapoptotic properties of commonly used inhalational anaesthetics, such as desflurane, sevoflurane and isoflurane, in equivalent doses. One study35 demonstrated that equipotent concentrations of the above mentioned three anaesthetics had similar neurotoxic profiles. Others, however, indicated some anaesthetic agents have a greater neurodegenerative effect.6,27,36,37 For example, Shen et al.27 showed that exposure of neonatal mice to 3% sevoflurane for 2 h daily for 3 days induced cognitive impairment and neuroinflammation, while similar exposure to 9% desflurane did not lead to developing brain toxicity. Liang et al.36 and Ramage et al.37 demonstrated that isoflurane caused greater neurodegeneration and memory deficit than an equivalent exposure to sevoflurane in the immature rodent brain. In addition, Kodama et al.6 reported that neonatal exposure to desflurane induced significantly greater neuroapoptosis than sevoflurane and isoflurane. Mice exposed to desflurane had substantially impaired working memory; however, performance in working memory tasks in mice exposed neonatally to sevoflurane or isoflurane was normal.6 The inconsistent results may be due to the different biologic indicators and behavioural test modules used in the experiments, the anaesthetic regimens and absolute concentrations administrated to animals, and even the strain diversity. Nevertheless, there are some studies indicating that inhaled anaesthetics might exert minor or no neurotoxic effect on the developing brain. Bercker et al.38 demonstrated that use of 3 to 5% sevoflurane for 6 h induced neither neurodegeneration nor learning deficits in neonatal rats. In addition, in an in-vitro study carried out by Berns et al.,39 up to 6 (8%) and 12 h (4%) exposure to sevoflurane, cell viability was the same when compared with untreated controls. Loepke et al.40 showed that isoflurane exposure led to increased immediate brain cell degeneration. However, neither significant reduction in neuronal density nor deficits in spontaneous locomotion, spatial learning or memory function affect neurobehavioural performances in the juvenile period.41
There are inconsistent data regarding the neuroapoptotic effects of xenon. Although some in-vivo and in-vitro studies reported that xenon alone was not neurotoxic,42,43 others indicated a proapoptotic property of xenon.44–46 Brosnan and Bickler46 presented recently that xenon was not neurotoxic at subminimum alveolar concentrations (MAC); however, it caused neurotoxicity at 1 MAC and greater concentrations. This is consistent with our finding that xenon provided maximal neuroprotective effect at 0.5 atm (∼0.53 MAC),47,48 but it reversed at higher pressures and exhibited significant neurotoxicity at 2 atm (∼2.1 MAC).49 Further research is required to identify a toxic/therapeutic ratio for xenon, as well as the mechanisms of xenon protection and toxicity.
Campbell et al.50 demonstrated that clinically relevant anaesthetic concentrations of ketamine, nitrous oxide and isoflurane had no significant neurotoxic effect applied individually or when given as an anaesthetic cocktail in vitro, even with an exposure up to 12 h. The author considered that neurotoxicity previously reported in vivo is not due to direct cytotoxicity of anaesthetic agents but results from other effects of the anaesthetised state during early brain development.50 Shu et al.5 discovered in their experiment that nociceptive stimulation augmented anaesthetic-induced neuroapoptosis and cognitive impairment. Another researcher showed that widespread brain cell death was generated by both isoflurane and carbon dioxide, and the degree and distribution of cell death was similar in isoflurane and carbon dioxide treated groups.51 Hypoglycaemia, however, did not seem to be responsible for the neurodegeneration, as dextrose supplementation failed to prevent neuronal loss in neonatal mice.40 Hence, many factors may exert additional effects on brain development including surgical stimulation, intraoperative pain and hypercapnia.
In summary, the majority of studies have linked inhaled anaesthetics to toxic effects in the brain after gestational or neonatal exposure. A time window of vulnerability exists when the brain grows rapidly during early development. Apoptotic neuronal death, influence on neurogenesis, impacts on synaptogenesis and axon guidance, glial cell impairment, neuroinflammation, cytosolic Ca2+ increase and mitochondrial dysfunction were identified as possible mechanisms of inhaled anaesthetic-induced developmental neurotoxicity. Furthermore, commonly used inhalational anaesthetics, such as desflurane, sevoflurane and isoflurane, were compared for the neuroapoptotic properties in equivalent doses in order to minimise the subsequent adverse outcomes. However, no anaesthetic appears to be superior. In addition to inhaled anaesthetics, the impacts of the anaesthetised state during early brain development, for example surgical stimuli, intraoperative pain as well as hypercapnia, demonstrated neurotoxicity in the immature brain.
Neuroprotective approaches to protect against inhaled anaesthetic-induced neurotoxicity
Considering the inhaled anaesthetic-induced deleterious effects in the central nervous system, attempts to protect the immature brain are of vital interest. The noble gas xenon has very rapid onset and recovery characteristics, as well as haemodynamic stability.52–54 Preconditioning with xenon prevented nitrous oxide and isoflurane-induced neuroapoptosis and cognitive deterioration, while hypoxic pretreatment exacerbated the toxicity of these anaesthetics, and nitrous oxide pretreatment had no effect.55 Early in life, α2 adrenoceptors could activate cellular survival mechanisms via endogenous norepinephrine, thus exerting a trophic role in central nervous system signalling.56,57 Acting as an α2 agonist, dexmedetomidine was shown to attenuate isoflurane-induced neuroapoptosis and provide neurocognitve protection in the immature brain.58,59 Hydrogen has recently received attention because of its ability to easily penetrate the blood–brain barrier as well as its antioxidant potential.60 It was determined in neonatal mice that hydrogen coadministered with sevoflurane reduced oxidative stress, neuronal apoptosis and subsequent neurobehavioural deficits.4 Furthermore, cotreatment with the mitochondrial-targeted antioxidant PPX or synthetic ROS scavenger EUK-134 significantly preserved mitochondrial integrity, downregulated lipid peroxidation, decreased neuronal loss and provided long-lasting protection against cognitive impairment in neonatal rats exposed to inhaled anaesthetics.31,61 The first identified endocannabinoid N-arachidonoylethanolamine (AEA) plays a crucial neuroprotective role in certain neurodegenerative diseases. NsTyr, an AEA analogue, was reported to protect immature brain against developmental sevoflurane neurotoxicity through MEK/extracellular signal-related kinases 1 and 2 (ERK1/2) MAPK signalling pathway.62 In addition, bumetanide, a specific inhibitor of chloride uptake, was shown to alleviate the epileptogenic and neurotoxic effects of sevoflurane in early postnatal rats by suppressing the excitatory output of sevoflurane-potentiated GABAA/glycine systems.63 Recombinant erythropoietin (rEPO) displayed a neuroprotective effect in isoflurane-induced mouse brain damage and learning impairments.64 Moreover, it was demonstrated that sevoflurane-induced long-term cognitive impairment was reversed by environmental enrichment (physical exercise, social interaction and environmental complexity) even when instituted with a 3-week delay after anaesthesia.13,27 In short, these experimental results provide several promising therapeutic strategies to alleviate neurotoxicity caused by inhalational anaesthesia exposure in the developing brain.
The protective profile of noble gases in perinatal hypoxic-ischaemic brain injury
Xenon is an inert gas that has proved to be efficient in clinical anaesthesia and is relatively devoid of clinically significant adverse haemodynamic properties.53,65 Results from various in-vitro and in-vivo animal studies have consistently demonstrated the neuroprotective effect of xenon.49,53,54,66 When administered after hypoxia-ischaemia in neonatal piglets and rats, treatment with xenon appreciably reduced cerebral magnetic resonance spectra (MRS) abnormalities and cell death markers, ameliorated histopathological outcomes and improved short and long-term neurological functions.67–69 Xenon also attenuated brain injury and exerted long-lasting functional neuroprotection when administrated before hypoxia-ischaemia insult.70,71 Zhuang et al.7 compared the protective profile of xenon and two other noble gases, argon and helium, in a rat neonatal asphyxia model. They demonstrated that all three inert gases improved cell survival, brain structural integrity and neurologic function at a juvenile age after moderate hypoxic-ischaemia. Argon improved cell survival to a naive level, whereas xenon and helium did not.7 Given that argon lacks a sedative effect and is highly cost-effective compared with xenon,54 future research should pursue argon neuroprotection. Some researchers have explored the protective efficiency of xenon in combination with other anaesthetic agents or techniques. A xenon/hypothermia regimen proved to have an additive neuroprotective effect after hypoxic-ischaemia than either treatment in isolation.68,69 Coadministration of lower doses of xenon and sevoflurane (20% + 0.75%) achieved a similar protective effect as either anaesthetic alone (75% xenon and 1.5% sevoflurane).70 Combined with the evidence described above concerning the potentially neurotoxic effects of xenon, further information is required to identify xenon's therapeutic window. This should be further identified from animal histologic and behavioural studies. In the meantime, if clinical trials are pursued, then subanaesthetic doses, which appear well tolerated from a neurotoxicity perspective, should be considered.
The protective profile of volatile anaesthetics in perinatal hypoxic-ischaemic brain injury
The volatile anaesthetics, such as desflurane, isoflurane and sevoflurane, have been proven to exert neuroprotection in various paradigms.72 The neuroprotective profile of isoflurane in perinatal hypoxic-ischaemic brain injury and the underlying mechanisms were studied by several researchers. Zhou et al.8 showed that isoflurane post-treatment decreased brain injury and improved long-term neurobehavioural outcomes; the effects were mediated by activating sphingosine-1-phosphate (S1P)/phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway. In the study by Sasaoka et al.,73 acute preconditioning of isoflurane in neonatal rats subjected to a hypoxic-ischaemic injury resulted in only transient neuroprotection. In in-vitro studies, preconditioning or postconditioning of isoflurane was demonstrated by McMurtrey and Li et al., 74,75 respectively. They showed that rat hippocampal neuronal damage was attenuated by inhibition of Ca2+/calmodulin-dependent protein kinases II (CaMKII) and NMDA receptors, activation of adenosine A2A receptors, upregulating of heme oxygenase-1 (HO-1) and activation of Erk1/2/hypoxia inducible factor (HIF)-1α pathway.74–76 Moreover, Luo et al.,70 Yang et al.71 and McAuliffe et al.72 proved that preconditioning with sevoflurane and desflurane demonstrated neuroprotective properties both in vitro and in vivo.These studies revealed that volatile anaesthetic agents may be advantageous when used for a defined period during the operative procedure.
The preclinical findings concerning the effects of inhaled anaesthetics on the developing brain are mixed. The existing data are not adequate for experts and clinicians to draw final conclusions. Therefore, additional research is needed to further identify this issue. Well designed preclinical research on this topic is particularly important. Several recommendations and guidelines, such as the Stroke Therapy Academic Industry Roundtable (STAIR) recommendations77 and the National Institute of Neurological Disorders and Stroke (NINDS) guidelines (http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf), have been published to improve the quality and utility of preclinical research. These fundamental principles should also apply to animal studies concerning anaesthetic-related effects on the immature brain. First of all, rigorous experimental design and transparent reporting are essential factors for high-quality studies; random allocation to treatment group; concealment of drug assignment and blinded assessment of outcome in order to eliminate randomisation and assessment bias; setting of the control groups should be adequate; a priori inclusion/exclusion criteria should be defined; appropriate power and sample size calculations should be performed and reported; dose–response results should be documented; reasons for excluding animals from the final data analysis should be announced; and all results, including negative and positive results, should be reported. Second, in order to obtain evidence that could guide clinical treatments effectively, animal experiments should be designed to closely mirror the clinical settings. Timing, dosage, duration and frequency of anaesthesia exposure should be carefully considered; both histological and behavioural outcomes should be assessed, and the effects of anaesthetics should be surveyed both acutely and long term; and relevant functional and biomarker endpoints should be included that could be also obtained in human trials. After initial evaluations in healthy male neonates, further studies should be carried out in females, animals with comorbid conditions and concomitant medications, as well as animals undergoing the most common surgical procedures required for young children, such as myringotomy and grommets for chronic ear infection, tonsillectomy, hernia repair and circumcision.78 Third, most of the preclinical studies were initially conducted in rodents. However, higher order species should also be tested. The data, especially the neurobehavioural outcomes in piglets and primates, are of great importance, as their brain development closely parallels humans.79 Fourth, in order to verify the reliability and stability of studies, the observed results should be reproducible in at least two independent laboratories.
The mechanisms of inhaled anaesthetic-induced neurotoxicity remain open to further research. The equivalence of the developmental status and the vulnerable time windows between animals and humans should be carefully assessed. In addition, noninvasive examinations and rapid diagnosis methods need to be developed.
Although robust preclinical results have shown that gestational and neonatal exposure to inhaled anaesthetics are deleterious to the developing brain, other studies indicated that the developmental neurotoxicity of inhalational anaesthetics is mild. Owing to the potential publication bias of the currently available articles, some studies showing no statistical significance might have been excluded. In addition, prospective clinical trials concerning the safety of general anaesthetics used in infants and children are difficult to conduct, as children cannot be ethically randomised to a ‘no anaesthesia’ group. Nonetheless, inhaled anaesthetics, such as desflurane, isoflurane and sevoflurane, are commonly used in paediatric anaesthesia. As a result, more animal studies are urgently needed to further clarify the effects of inhalational anaesthetics on the developing brain. Despite the difficult path to translate experimental results into clinical applications, research must address the mechanisms of injury to identify potential therapeutic targets. However, as suggested by the SmartTots consensus statement (http://www.smarttots.org/resources/consensus.html), which considers the safety of anaesthetics and sedative agents administered to infants and young children and is endorsed by several communities including ESA and ASA, the risks and benefits of procedures requiring anaesthetics as well as the known health risks of not treating certain conditions should be judged and weighed carefully. Meanwhile, preclinical data suggest a benefit from noble gas and volatile anaesthetic-induced neuroprotection in perinatal hypoxic-ischaemic brain injury. In addition to some ongoing clinical trials (such as TOBYXe, NCT00934700; CoolXenon2, NCT01545271), more studies are needed to assess the safety and efficacy profiles of these potential therapies.
Acknowledgements relating to this article
Assistance with the review: none.
Financial support and sponsorship: Jingjin Liu is supported by the Overseas Study Program of Guangzhou Elite Project.
Conflicts of interest: none.
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