Abstract
Millions of children undergo surgical operations and painful interventions with general anesthesia every year. Animal research has demonstrated structural and functional consequences following exposure early in life. Epidemiological studies have associated early childhood anesthetic exposure for surgery with subsequent neurobehavioral abnormalities. Combined, these findings have raised substantial concerns that anesthetics may interfere with brain development in humans. However, several important questions remain unresolved, such as whether structural abnormalities occur in humans, the exact neurocognitive phenotype following exposure, whether age during exposure affects vulnerability, and if there even exists a safe age after which the brain becomes resistant to long-term alterations by anesthetics. Complicating this discussion is the fact that anesthetics also protect the immature brain from the noxious effects of stress, pain, and ischemia. Accordingly, this review discusses the current state of research into this ambiguity, the yin and yang of anesthetic effects on the developing brain.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
General anesthesia represents one of the most profound discoveries in medicine, allowing millions of patients, including fetuses, neonates, infants, and children, to undergo surgical procedures every year without recollection of the otherwise traumatic perioperative events [1, 2]. Anesthetics alleviate the noxious stimulation of stress and pain that can adversely impact the developing brain [3]. Moreover, emerging animal studies have examined anesthetics’ protective properties during hypoxic–ischemic brain injury, while the longevity and clinical relevance of these data remains to be determined [4].
Conversely, recent animal and epidemiological studies have implicated anesthetics to potentially harm the immature brain [5], raising substantial safety concerns regarding their use in young children. More than 200 studies in a wide variety of animal species have now documented adverse effects following exposure to all routinely used general anesthetics and sedatives [6•]. Short-term neurotoxic effects include structural injury, such as neuronal and oligodendrocyte cell death, dendritic abnormalities, alterations in trophic factors, and mitochondrial damage, while long-term abnormalities manifest in learning impairment and memory deficits. While these structural abnormalities are not easily verified in humans, disturbingly, several epidemiological studies in children have associated exposures to anesthesia for surgery early in life with long-term neurodevelopmental abnormalities, such as diminished school performance and learning deficiencies. Combined, these findings from laboratory and clinical studies have raised substantial concerns regarding the safe use of anesthetics in children.
Accordingly, the current review discusses these contrasting properties, the yin and yang of anesthetic effects on the developing brain, in order to consider the implications for clinical pediatric anesthesia practice.
Anesthetic Neurotoxicity: The Yin
The potentially deleterious effects of anesthetic exposure early in life arguably represent one of the greatest challenges for pediatric anesthesiology and possibly for the entire field of anesthesiology [7•]. The rapid progression of research is largely driven by animal studies, which have expanded more than fivefold in the past 7 years [6•, 8].
Brain Structural Abnormalities in Developing Animals
All clinically utilized anesthetics are thought to alter awareness by stimulating γ-aminobutyrate (GABAA) receptors and/or blocking N-methyl-d-aspartate (NMDA) receptors. However, the balance between these receptors is also critically important during brain development [9, 10]. While speculative, it seems conceivable that interference with the crosstalk of excitatory and inhibitory neurotransmission during anesthetic exposure may lead to aberrations in brain development. Importantly, development does not occur uniformly across the entire mammalian central nervous system but rather varies in timing and duration by brain region, brain cell type, and species. The human brain experiences a considerable increase in the number of cells in utero and during early postnatal life. In small rodents, neurogenesis peaks around birth, albeit during a matter of days. This surge in neuronal birth is followed by a substantial elimination of superfluous neurons during the first few years or days of life, in humans or rodents, respectively [11], combined with an increase in myelination by oligodendrocytes. In certain brain regions, such as the hippocampal dentate gyrus and olfactory bulb, neurogenesis and deletion of new neurons continue throughout life, both in small rodents and higher order mammals. The elimination of superfluous neurons, which represents an integral part of brain development to avert malformations and intrauterine demise [12], occurs by an energy-consuming cellular suicide program termed programmed cell death or apoptosis [13]. This suicide program is an energy-consuming process that is built into every mammalian cell [14]. Subsequent to growing in number, neurons form an excess amount of connections during a phase of rapid synaptogenesis, which dependent on brain region peaks between 3 and 15 months of age in humans or during weeks 2 to 4 of life in small rodents [15, 16]. Similar to the elimination of neuronal cells, these connections are reduced by 50 % into adulthood [17].
In animals, anesthetic exposure has been found to dramatically increase apoptotic cell death, compared with the naturally occurring neuronal degeneration in unanesthetized control animals, in some instances by more than 60-fold. This process has been observed after exposure to a diverse group of anesthetics and sedatives, such as clonazepam, diazepam, midazolam, pentobarbital, ketamine, propofol, desflurane, halothane, isoflurane, sevoflurane, and xenon (most recently reviewed in [6•]). However, while exposure to isoflurane, for example, can increase neuroapoptosis by more than 20-fold compared with natural cell death, the percentage of neurons affected, even following a prolonged exposure, may be less than 3 %, as measured in neonatal mice [18].
The exact cellular mechanism for anesthesia-induced neuroapoptosis remains unresolved. However, as a potential underlying mechanism, neuronal elimination has been linked to diminution of brain-derived neurotrophic factor (BDNF) [19–21], a protein integral to neuronal survival, growth, and differentiation. Moreover, prolonged isoflurane exposure in newborn rats induces mitochondrial ultrastructural abnormalities [22], which have been successfully alleviated by coadministration of mitochondrial oxygen-free radical scavengers [23]. Other potentially underlying mechanisms are actively being investigated.
Other brain cell families are also affected by anesthetic exposure in developing animals. In newborn non-human primates, similar degenerative effects have been observed in oligodendrocytes, the myelin sheath-forming glial brain cells [24]. Prolonged anesthetic exposure also impairs growth of immature astrocytes and delays their maturation in vitro but does not seem to affect their viability [25]. Volatile anesthetic exposure during the first 2 weeks of life in rodents has also been found to decrease synaptic and dendritic spine density [26, 27], while exposure after 14 days of age increases dendritic branching [27]. The exact mechanism behind this age-dependent dichotomy remains to be determined.
Given the considerable concern for structural abnormalities observed in immature animals during anesthetic exposure being applicable to the developing human brain, substantial laboratory research efforts have been devoted to devising mitigating strategies, spanning from supplemental anesthetics or sedatives, over adjuvant therapies, to drugs targeting cell death pathways. The sedative dexmedetomidine and the anesthetic xenon have been found to reduce isoflurane-induced neuroapoptosis [28–30]. Interestingly, a brief exposure to isoflurane protected from a subsequent prolonged, otherwise injurious isoflurane exposure in an in vitro model [31]. Protective adjuvant therapies that have been tested to alleviate deleterious anesthetic effects have included L-carnitine [32], β-estradiol [19], or melatonin [33]. Targeted strategies have been successfully directed at the endoplasmic reticular IP3 receptor [34], the inhibition of nitric oxide synthase [35], the activity-dependent neuroprotective protein (ADNP) and vitamin D3 [36], the tissue plasminogen activator, plasmin, or the neurotrophic receptor p75NTR [20], as well as the RhoA receptor or by preventing cytoskeletal depolymerization with either jasplakinolide or TAT-Pep5 [37]. Mitochondrial protection with pramipexole during neonatal exposure to isoflurane, nitrous oxide, and midazolam improved retention of memory tasks in adult rats [38]. Moreover, concomitant administration of erythropoietin during a neonatal anesthetic exposure prevented sevoflurane-induced neuronal apoptosis and behavioral and learning abnormalities in adulthood [39]. Other pharmacological therapies that have decreased the neuroapoptotic effects of anesthetics include lithium [40] and bumetanide [41]. However, at this point, it is premature to recommend any of these experimental treatments for study in children.
Long-Term Cognitive Outcome in Animals
An important question, which is whether any of the observed structural abnormalities are causatively linked to long-term behavioral or cognitive outcomes is a matter of continued investigation. Some form of neurological abnormality has been observed in juvenile and young adult mice and rats, after exposure to enflurane, halothane, isoflurane, sevoflurane, propofol, ketamine, or a combination of isoflurane, nitrous oxide, and midazolam in their infancy (reviewed in [6•]). However, these studies were not able to identify a specific pattern of cognitive deficits. Several have demonstrated learning and memory problems in the Morris water maze, while other tests of behavior and learning, such as acoustic startle response or radial arms maze tests, appeared unaffected even in the same animals [42]. Also, several other studies were unable to demonstrate any neurological abnormalities after neonatal anesthetic administration (reviewed in [6•]). It is a matter of great concern that long-lasting cognitive and motivational deficits have now also been observed in non-human primates after a 24-h ketamine exposure early in life [43••]. Additional primate studies using more commonly used anesthetics are currently being performed but are complicated by the fact that it is currently unclear which specific neurological domains might be affected by anesthetic exposure and whether other factors, such as surgical stimulation, play a role in any subsequent neurological outcome.
Behavioral and Cognitive Outcome in Children
Given the potentially dramatic consequences for children having to undergo life-saving or quality-of-life-improving surgeries with anesthesia early in life, it is of utmost importance to assess the clinical applicability of the available animal data. For obvious reasons, however, brain structure cannot be easily assessed in young children after anesthetic exposure. Several studies that were not designed to evaluate the effects of pediatric surgery with anesthesia have utilized cognitive assessments, oftentimes years removed from the exposure. Several have demonstrated behavioral abnormalities, diminished cognition, and learning abnormalities, particularly in especially vulnerable patient populations, such as those suffering from congenital malformations, concomitant illnesses, or extreme prematurity (reviewed in [8]). However, within the past 5 years, several epidemiological studies have focused on healthier surgical patients to investigate the effects of anesthetic exposures prior to 3–4 years of age on subsequent school performance and learning abilities (Table 1).
Several of these retrospective studies have demonstrated repeated exposures to anesthetics prior to 3–4 years of age to be associated with an increased risk of subsequent learning disabilities, a need for individualized speech or language therapy, or an increase in the incidence of developmental or behavioral disorders, when compared to the general population or to peers matched for known confounders [46, 50, 52]. Conversely, a brief anesthetic exposure during surgical delivery for Cesarean section did not carry the same risk for neurodevelopmental abnormalities [47, 51].
Other studies did not find a detrimental effect of anesthetic exposure on subsequent academic performance, compared with the national average [54, 58], or any differences between monozygotic twins that were discordant for anesthetic exposure early in life [49]. Interestingly, school performance was identical within twin pairs discordant for anesthetic exposure, meaning one twin was exposed while the other one was not. This suggests that other factors, such as genetics or environment, may have influenced the results [49]. However, the assessment tools of the aforementioned studies differed widely, which may explain, at least in part, the disparate results.
Along those lines, a recent study comparing several assessment modalities of cognitive function found that a single anesthetic exposure in children in the Western Australian Pregnancy Cohort (Raine study) did not negatively impact academic performance, behavior, or motor function, but directly administered neuropsychological tests uncovered deficits in language development and abstract reasoning, compared with previously unexposed children [55•, 62••].
Accordingly, while some evidence suggests that an anesthetic exposure for surgery early in life may be associated with subsequent abnormalities, especially when cognitive performance was individually assessed, several other studies failed to identify an abnormal neurological phenotype of anesthetic exposure in young children. Importantly, the retrospective cohort study design of all currently available studies cannot distinguish the relative contributions of surgery, anesthesia, pain, or inflammation on any of the observed outcomes.
Age Dependence of Anesthetic Neurotoxicity
Apart from the choice of neurocognitive assessment tool, another potential reason for the seemingly conflicting observations regarding neurological abnormalities in children may be the age during anesthetic exposure. Previous animal research observed brain structural abnormalities after anesthetic exposure in very young animals, e.g., neuronal and synaptic elimination in 1-week-old rodents, in brain regions where neurogenesis peaks early in development [26, 64]. Recent data indicate that structural abnormalities also extend into later stages of brain development in regions with later peaks in neurogenesis [27, 65••], potentially even into adulthood [66••, 67•]. The anesthetic effects differ dramatically depending on the age of the animals, possibly due to the maturational stage of the particular neurons; synaptic density is decreased after anesthesia in the immediate postnatal period, while it is increased if exposure occurs at a later stage [26, 27]. It may therefore be reasonable to speculate that anesthetics affect brain cells differently, dependent on their maturational state during exposure. This would be consistent with recent observations in animals that neuronal vulnerability to anesthesia-induced neurodegeneration peaks around 2 weeks after neuronal birth and that brain regional vulnerability pattern may closely follow the peak of neurogenesis in the respective regions [65••, 67•]. If these findings were applied to children undergoing anesthesia, it seems reasonable to believe that exposure would particularly disrupt both neuronal generation and synapse formation that is specific to the particular age and to the neurocognitive domain being developed at the time of exposure [68]. Accordingly, anesthetic exposures in the neonatal period might particularly affect sensory development, whereas those in late infancy could alter language development. In turn, exposure in childhood might interfere with higher cognition [69]. Additional research, both clinical and in the laboratory, is urgently needed to investigate this very important matter for public health.
Ongoing Clinical Research into the Effects of Anesthesia on Neurodevelopment
In order to address some of the limitations of epidemiological analyses, several prospective studies are ongoing. The GAS study represents an international, multi-center trial that randomized more than 700 infants undergoing inguinal hernia repair to either general or spinal anesthesia [70]. Neurocognitive performance is being tested at 2 and 5 years of age using a battery of individually administered tests, and results are anticipated to be available around 2016.
Another approach has been taken by the Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA) study, which retrospectively identifies children who underwent inguinal hernia repair before their 3rd birthday and prospectively tests their attention, executive function, language, learning, memory, sensorimotor development, social perception, and visuospatial processing using the NEPSY II testing tool, comparing them with unexposed siblings [71]. Initial results of the PANDA study are expected in 2015.
Similarly, the Mayo Anesthetic Safety in Kids (MASK) study, uses a birth cohort to prospectively assess neurological performance by utilizing an extensive battery of neurocognitive tests in children previously exposed to one or multiple anesthetics before 3 years of age, compared with those who were never exposed to anesthesia [72]. The MASK study has started enrolling and testing children, and preliminary results are expected in 1–2 years.
An international, prospective, multi-center trial, the T-REX study, is currently being prepared to randomize patients undergoing urological procedures with caudal epidural analgesia to an anesthetic of either sevoflurane or the combination of dexmedetomidine and remifentanil. However, the prospective nature of this trial and the need for a long-term neurological assessment means that results will be a number of years away.
Anesthetic Neuroprotection: The Yang
In the discussion about the potential harmful effects of anesthetics on the developing brain, one should not lose sight of the fact that anesthetics are administered to block some of the potent noxious stimuli patients are exposed to during the perioperative period, such as stress and pain. Untreated, these stressors have repeatedly been found to lead to long-term neurological abnormalities, both in animals and humans.
Deleterious Effects of Pain on the Developing Brain
In animals, repetitive painful stimulation in the neonatal period can lead to immediate neurodegeneration [73], long-term local sensory hyperinnervation [74], hyperalgesia [75], and behavioral abnormalities [76], as well as alterations in pain thresholds [77], pain processing, and sensory perception [78]. Moreover, repetitive acute pain early in life increases subsequent vulnerability to stress and anxiety disorders, as well as chronic pain behaviors [79, 80]. Even adverse emotional experiences in early life have been linked to long-lasting abnormalities, including imbalances of the inhibitory nervous system [81], impaired development of the nociceptive system and behavioral abnormalities [82], as well as persistent learning impairment [83].
Clinical studies have established that perioperative stress and painful stimulation increase catecholamines, cortisol, endorphins, glucagon, and growth hormone substantively [84–86]. Some of these markers may be increased for several years after the insult [86]. While several of these studies were performed in neonates undergoing cardiac surgery, even painful stimulation during less invasive procedures early in life, such as circumcision, can lead to exaggerated pain responses later in life [87]. Impaired cognitive and motor impairment in toddlers have been linked to previous painful stimulations when they were cared for as premature infants [88].
Adequate Anesthesia/Analgesia Prevents Deleterious Effects of Pain
Providing adequate analgesia and anesthesia ameliorates many of the deleterious effects of pain-related stress [73, 75, 80, 83]. Adequate anesthesia and analgesia, including regional techniques, inhibit perioperative stress and improve postoperative outcomes [89–92]. Providing levels of anesthesia and anesthesia adequate for the severity of the stressful stimulus reduced the incidence of several complications, such as sepsis, disseminated intravascular coagulation, and mortality [93]. Adequate analgesia during circumcision early in life not only blunts the immediate humoral stress response, but also alleviates the long-term, pain-induced hyperalgesia observed in boys not provided adequate pain control [87, 94].
Taken together, these data in animals and humans suggest that painful stimulation and stress during early brain development can lead to long-term deleterious consequences and that adequate anesthesia and analgesia provided during painful insults can protect the developing brain from these undesirable effects and improve outcome. However, the exact nature of the interactions between anesthesia and surgery clearly requires further laboratory and clinical research.
Anesthetic Neuroprotection During Brain Ischemia
A topic of intense investigation is the potential protective properties of anesthetics during episodes of inadequate blood flow and oxygenation to the brain. The developing brain has historically been considered less vulnerable to ischemia than the mature brain [95]. However, significant neurological impairment occurs not infrequently in patients at increased risk for hypoxic–ischemic injury during the perioperative period, such as survivors of complex congenital heart surgery [96, 97]. While most studies into the protective effects of anesthetics have been conducted in adult animals, immature hypoxia–ischemia models have also been used, emulating birth asphyxia or hypothermic infant cardiac surgery. Similar to findings in mature animals, these studies found inhaled anesthetic strategies, including desflurane, isoflurane, sevoflurane, or xenon, to reduce brain structural injury within 1 week after the ischemic insult [98–104, 105•]. Moreover, our laboratory has recently demonstrated the long-term neurocognitive protective properties of a combination protective strategy of sevoflurane and mild hypothermia [105•]. The potential mechanisms of the protective effects of anesthetics may include a reduction in excitotoxicity by blocking NMDA receptors and activating GABA receptors.
While additional laboratory research is needed, these findings suggest that anesthetics might be useful in clinical settings of increased risk for perioperative hypoxia–ischemia.
Conclusions
Anesthetics are widely used in modern clinical practice to allow complex surgical operations and facilitate otherwise stressful and painful procedures. In this process, anesthetics alleviate the deleterious effects of unabated stress and pain on the developing brain. Emerging laboratory research suggests a potential role in protective strategies during hypoxic–ischemic episodes early in life, whereas clinical data are absent. Conversely, numerous animal studies using a wide variety of species have also documented deleterious effects following anesthetic exposure. While neuronal cell death and dendritic alterations have been widely described, long-term neurocognitive abnormalities have not consistently been observed. Results from human epidemiological studies are similarly equivocal, with some demonstrating abnormal behavior and learning impairment following surgery with anesthesia early in life, while others have not. Some of these inconsistencies in demonstrating a neurological correlate may be explained by the sensitivity of neurocognitive tests utilized. Alternatively, if anesthetics exerted their disruptive effects specifically on immature neurons and developing networks, the discrepant findings could be the result of the varying ages during exposure across studies and the current ignorance regarding the potentially related neurocognitive phenotype. Importantly, however, the retrospective nature of all the currently available clinical data precludes making any definitive causative links between neurological abnormalities and surgery, pain, inflammation, or anesthetic exposures.
Given these uncertainties, it would be unethical to withhold anesthetics and sedatives during painful procedures in children and unwise to change clinical practice to anesthetic techniques with unproven safety record. Given the known and oftentimes serious risks of not performing or postponing urgent surgical procedures, the potential risks of anesthetic exposure have to be balanced against the benefits of performing life-saving and quality-of-life-preserving operations. Inadequate levels of anesthesia and analgesia are clearly deleterious and need to be avoided. However, given the potential consequences for the individual and for society, intensified research efforts should focus on elucidating the mechanisms of the deleterious effects of anesthetics on the developing brain, assessing its clinical relevance, and devising mitigating strategies.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
DeFrances CJ, Cullen KA, Kozak LJ. National hospital discharge survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat. 2007;13:1–209.
Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008;372:139–44.
Loepke AW, Davidson AJ. Surgery, anesthesia, and the developing brain. In: Coté CJ, Lerman J, Anderson B, editors. A practice of anesthesia for infants and children: expert consult—online and print. 5th ed. Philadelphia: W. B. Saunders; 2012. p. 492–509.
Ward CG, Loepke AW. Anesthetics and sedatives: toxic or protective for the developing brain? Pharmacol Res. 2011;65:271–4.
Lin EP, Soriano SG, Loepke AW. Anesthetic neurotoxicity. Anesthesiol Clin. 2014;32:133–55.
• Deng M, Loepke AW. Anesthetic neurotoxicity: preclinical and clinical research. J Perioper Sci. 2014;1:1–49. Most recent, exhaustive literature review regarding laboratory and clinical studies into anesthetic neurotoxicity, documenting a 5-fold increase in the number of articles within the past 7 years.
• Rappaport BA, Suresh S, Hertz S, et al. Anesthetic neurotoxicity: clinical implications of animal models. N Engl J Med. 2015;372:796–7. Editorial statement including researchers at the Food and Drug Administration (FDA) delineating the concerns regarding the adverse effects of anesthetic agents on neurological development in young children.
Loepke AW, Soriano SG. An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008;106:1681–707.
Penn AA, Shatz CJ. Brain waves and brain wiring: the role of endogenous and sensory-driven neural activity in development. Pediatr Res. 1999;45:447–58.
de Lima AD, Opitz T, Voigt T. Irreversible loss of a subpopulation of cortical interneurons in the absence of glutamatergic network activity. Eur J Neurosci. 2004;19:2931–43.
Bayer SA, Altman J, Russo RJ, et al. Timetables of neurogenesis in the human brain based on experimentally determined patterns in the rat. Neurotoxicology. 1993;14:83–144.
Kuida K, Zheng TS, Na S, et al. Decreased apoptosis in the brain and premature lethality in cpp32-deficient mice. Nature. 1996;384:368–72.
Kuan CY, Roth KA, Flavell RA, et al. Mechanisms of programmed cell death in the developing brain. Trends Neurosci. 2000;23:291–7.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–57.
Crain B, Cotman C, Taylor D, et al. A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Res. 1973;63:195–204.
De Felipe J, Marco P, Fairen A, et al. Inhibitory synaptogenesis in mouse somatosensory cortex. Cereb Cortex. 1997;7:619–34.
Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Compd Neurol. 1997;387:167–78.
Istaphanous GK, Howard J, Nan X, et al. Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology. 2011;114:578–87.
Lu LX, Yon JH, Carter LB, et al. General anesthesia activates bdnf-dependent neuroapoptosis in the developing rat brain. Apoptosis. 2006;11:1603–15.
Head BP, Patel HH, Niesman IR, et al. Inhibition of p75 neurotrophin receptor attenuates isoflurane-mediated neuronal apoptosis in the neonatal central nervous system. Anesthesiology. 2009;110:813–25.
Pontén E, Fredriksson A, Gordh T, et al. Neonatal exposure to propofol affects bdnf but not camkii, gap-43, synaptophysin and tau in the neonatal brain and causes an altered behavioural response to diazepam in the adult mouse brain. Behav Brain Res. 2011;223:75–80.
Sanchez V, Feinstein SD, Lunardi N, et al. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology. 2011;115:992–1002.
Boscolo A, Milanovic D, Starr JA, et al. Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain. Anesthesiology. 2013;118:1086–97.
Brambrink A, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72:525–35.
Lunardi N, Hucklenbruch C, Latham JR, et al. Isoflurane impairs immature astroglia development in vitro: the role of actin cytoskeleton. J Neuropathol Exp Neurol. 2011;70:281–91.
Lunardi N, Ori C, Erisir A, et al. General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats. Neurotox Res. 2010;17:179–88.
Briner A, Nikonenko I, De Roo M, et al. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology. 2011;115:282–93.
Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. Anesthesiology. 2007;106:746–53.
Cattano D, Williamson P, Fukui K, et al. Potential of xenon to induce or to protect against neuroapoptosis in the developing mouse brain. Can J Anaesth. 2008;55:429–36.
Sanders RD, Sun P, Patel S, et al. Dexmedetomidine provides cortical neuroprotection: impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiol Scand. 2010;54:710–6.
Wei H, Liang G, Yang H. Isoflurane preconditioning inhibited isoflurane-induced neurotoxicity. Neurosci Lett. 2007;425:59–62.
Zou X, Sadovova N, Patterson TA, et al. The effects of l-carnitine on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex. Neuroscience. 2008;151:1053–65.
Yon JH, Carter LB, Reiter RJ, et al. Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis. 2006;21:522–30.
Wang QJ, Li KZ, Yao SL, et al. Different effects of isoflurane and sevoflurane on cytotoxicity. Chin Med J. 2008;121:341–6.
Wang C, Sadovova N, Patterson TA, et al. Protective effects of 7-nitroindazole on ketamine-induced neurotoxicity in rat forebrain culture. Neurotoxicology. 2008;29:613–20.
Turner CP, Gutierrez S, Liu C, et al. Strategies to defeat ketamine-induced neonatal brain injury. Neuroscience. 2012;210:384–92.
Lemkuil BP, Head BP, Pearn ML, et al. Isoflurane neurotoxicity is mediated by p75NTR-rhoa activation and actin depolymerization. Anesthesiology. 2011;114:49–57.
Boscolo A, Ori C, Bennett J, et al. Mitochondrial protectant pramipexole prevents sex-specific long-term cognitive impairment from early anaesthesia exposure in rats. Br J Anaesth. 2013;110(Suppl 1):i47–52.
Pellegrini L, Bennis Y, Velly L, et al. Erythropoietin protects newborn rat against sevoflurane-induced neurotoxicity. Paediatr Anaesth. 2014;24:749–59.
Straiko MM, Young C, Cattano D, et al. Lithium protects against anesthesia-induced developmental neuroapoptosis. Anesthesiology. 2009;110:862–8.
Edwards DA, Shah HP, Cao W, et al. Bumetanide alleviates epileptogenic and neurotoxic effects of sevoflurane in neonatal rat brain. Anesthesiology. 2010;112:567–75.
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;23:876–82.
•• Paule MG, Li M, Allen RR, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33:220–30. First study demonstrating long-standing impairments in cognitive abilities and motivation in non-human primates following a neonatal, albeit prolonged, exposure to ketamine.
Rozé JC, Denizot S, Carbajal R, et al. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the epipage cohort. Arch Pediatr Adolesc Med. 2008;162:728–33.
Kalkman CJ, Peelen L, Moons KG, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110:805–12.
Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110:796–804.
Sprung J, Flick RP, Wilder RT, et al. Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;111:302–10.
DiMaggio CJ, Sun LS, Kakavouli A, et al. A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21:286–91.
Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12:246–53.
DiMaggio C, Sun L, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113:1143–51.
Flick RP, Lee K, Hofer RE, et al. Neuraxial labor analgesia for vaginal delivery and its effects on childhood learning disabilities. Anesth Analg. 2011;112:1424–31.
Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128:e1053–61.
Garcia Guerra G, Robertson CM, Alton GY, et al. Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21:932–41.
Hansen TG, Pedersen JK, Henneberg SW, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114:1076–85.
• Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476–8. Epidemiological study demonstrating abnormalities in language development and cognition following a single anesthetic exposure under 3 years of age.
Block RI, Thomas JJ, Bayman EO, et al. Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117:494–503.
Filan PM, Hunt RW, Anderson PJ, et al. Neurologic outcomes in very preterm infants undergoing surgery. J Pediatr. 2012;160:409–14.
Hansen TG, Pedersen JK, Henneberg SW, et al. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatr Anaesth. 2013;23:883–90.
Fan Q, Cai Y, Chen K, et al. Prognostic study of sevoflurane-based general anesthesia on cognitive function in children. J Anesth. 2013;27:493–9.
Andropoulos DB, Ahmad HB, Haq T, et al. The association between brain injury, perioperative anesthetic exposure, and 12-month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. Paediatr Anaesth. 2014;24:266–74.
Garcia Guerra G, Robertson CM, Alton GY, et al. Neurotoxicity of sedative and analgesia drugs in young infants with congenital heart disease: 4-year follow-up. Paediatr Anaesth. 2014;24:257–65.
•• Ing CH, DiMaggio CJ, Malacova E, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology. 2014;120:1319–32. Important comparison of different outcomes measures assessing neurological function following surgery with anesthesia in early childhood.
• Stratmann G, Lee J, Sall JW, et al. Effect of general anesthesia in infancy on long-term recognition memory in humans and rats. Neuropsychopharmacology. 2014;39:2275–87. First clinical study demonstrating abnormalities in memory tasks in children prospectively tested following surgery with anesthesia prior to their second birthday.
Yon JH, Daniel-Johnson J, Carter LB, et al. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience. 2005;135:815–27.
•• Hofacer RD, Deng M, Ward CG, et al. Cell age-specific vulnerability of neurons to anesthetic toxicity. Ann Neurol. 2013;73:695–704. Animal study demonstrating that isoflurane exposure induces neuronal cell death in young and adult rodents, suggesting that neuronal age, rather than simply age of the individual affects vulnerability to anesthetic neurotoxicity.
•• Krzisch M, Sultan S, Sandell J, et al. Propofol anesthesia impairs the maturation and survival of adult-born hippocampal neurons. Anesthesiology. 2013;118:602–10. Laboratory study proving deleterious effects of propofol exposure on neuronal maturation and survival in adult rodents.
• Deng M, Hofacer RD, Jiang C, et al. Brain regional vulnerability to anaesthesia-induced neuronal cell death shifts with age during exposure and extends into adulthood for some regions. Br J Anaesth. 2014;113:443–51. Rodent study introducing the concept that brain regions are differentially affected by anesthesia-induced neurodegeneration dependent on their relative peaks in neurogenesis.
Taliaz D. Skills development in infants: a possible role for widespread neurogenesis? Front Behav Neurosci. 2013;7:178.
Bardin J. Neurodevelopment: unlocking the brain. Nature. 2012;487:24–6.
Davidson AJ, McCann ME, Morton NS, et al. Anesthesia and outcome after neonatal surgery: the role for randomized trials. Anesthesiology. 2008;109:941–4.
Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010;105(Suppl 1):i61–8.
Nemergut ME, Aganga D, Flick RP. Anesthetic neurotoxicity: what to tell the parents? Paediatr Anaesth. 2014;24:120–6.
Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res. 2007;62:283–90.
Reynolds ML, Fitzgerald M. Long-term sensory hyperinnervation following neonatal skin wounds. J Compd Neurol. 1995;358:487–98.
LaPrairie JL, Johns ME, Murphy AZ. Preemptive morphine analgesia attenuates the long-term consequences of neonatal inflammation in male and female rats. Pediatr Res. 2008;64:625–30.
Bhutta AT, Rovnaghi C, Simpson PM, et al. Interactions of inflammatory pain and morphine in infant rats: long-term behavioral effects. Physiol Behav. 2001;73:51–8.
Anand KJ, Coskun V, Thrivikraman KV, et al. Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav. 1999;66:627–37.
Ruda MA, Ling QD, Hohmann AG, et al. Altered nociceptive neuronal circuits after neonatal peripheral inflammation. Science. 2000;289:628–31.
Sternberg WF, Scorr L, Smith LD, et al. Long-term effects of neonatal surgery on adulthood pain behavior. Pain. 2005;113:347–53.
LaPrairie JL, Murphy AZ. Female rats are more vulnerable to the long-term consequences of neonatal inflammatory injury. Pain. 2007;132(Suppl 1):S124–33.
Helmeke C, Ovtscharoff W Jr, Poeggel G, et al. Imbalance of immunohistochemically characterized interneuron populations in the adolescent and adult rodent medial prefrontal cortex after repeated exposure to neonatal separation stress. Neuroscience. 2008;152:18–28.
Rokyta R, Yamamotova A, Slamberova R, et al. Prenatal and perinatal factors influencing nociception, addiction and behavior during ontogenetic development. Physiol Res. 2008;57(Suppl 3):S79–88.
Boasen JF, McPherson RJ, Hays SL, et al. Neonatal stress or morphine treatment alters adult mouse conditioned place preference. Neonatology. 2009;95:230–9.
Anand KJ, Brown MJ, Causon RC, et al. Can the human neonate mount an endocrine and metabolic response to surgery? J Pediatr Surg. 1985;20:41–8.
Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses in neonates undergoing cardiac surgery. Anesthesiology. 1990;73:661–70.
Grunau RE, Haley DW, Whitfield MF, et al. Altered basal cortisol levels at 3, 6, 8 and 18 months in infants born at extremely low gestational age. J Pediatr. 2007;150:151–6.
Taddio A, Katz J, Ilersich AL, et al. Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet. 1997;349:599–603.
Grunau RE, Whitfield MF, Petrie-Thomas J, et al. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain. 2009;143:138–46.
Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet. 1987;1:62–6.
Anand KJ, Sippell WG, Schofield NM, et al. Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation? Br Med J. 1988;296:668–72.
Wolf AR, Eyres RL, Laussen PC, et al. Effect of extradural analgesia on stress responses to abdominal surgery in infants. Br J Anaesth. 1993;70:654–60.
Rao SC, Pirie S, Minutillo C, et al. Ward reduction of gastroschisis in a single stage without general anaesthesia may increase the risk of short-term morbidities: results of a retrospective audit. J Paediatr Child Health. 2009;45:384–8.
Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992;326:1–9.
Stang HJ, Gunnar MR, Snellman L, et al. Local anesthesia for neonatal circumcision. Effects on distress and cortisol response. JAMA. 1988;259:1507–11.
Keelan J, Bates TE, Clark JB. Heightened resistance of the neonatal brain to ischemia-reperfusion involves a lack of mitochondrial damage in the nerve terminal. Brain Res. 1999;821:124–33.
Hövels-Gürich HH, Seghaye MC, Schnitker R, et al. Long-term neurodevelopmental outcomes in school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg. 2002;124:448–58.
Hövels-Gürich HH, Bauer SB, Schnitker R, et al. Long-term outcome of speech and language in children after corrective surgery for cyanotic or acyanotic cardiac defects in infancy. Eur J Paediatr Neurol. 2008;12:378–86.
Kurth CD, Priestley M, Watzman HM, et al. Desflurane confers neurologic protection for deep hypothermic circulatory arrest in newborn pigs. Anesthesiology. 2001;95:959–64.
Loepke AW, Priestley MA, Schultz SE, et al. Desflurane improves neurologic outcome after low-flow cardiopulmonary bypass in newborn pigs. Anesthesiology. 2002;97:1521–7.
Zhao P, Zuo Z. Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats. Anesthesiology. 2004;101:695–703.
Zhao P, Peng L, Li L, et al. Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats. Anesthesiology. 2007;107:963–70.
McAuliffe JJ, Joseph B, Vorhees CV. Isoflurane-delayed preconditioning reduces immediate mortality and improves striatal function in adult mice after neonatal hypoxia-ischemia. Anesth Analg. 2007;104:1066–77.
Luo Y, Ma D, Leong E, et al. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology. 2008;109:782–9.
McAuliffe JJ, Loepke AW, Miles L, et al. Desflurane, isoflurane, and sevoflurane provide limited neuroprotection against neonatal hypoxia-ischemia in a delayed preconditioning paradigm. Anesthesiology. 2009;111:533–46.
• Lin EP, Miles L, Hughes EA, et al. A combination of mild hypothermia and sevoflurane affords long-term protection in a modified neonatal mouse model of cerebral hypoxia-ischemia. Anesth Analg. 2014;119:1158–73. Report of a novel animal model of neonatal brain ischemia, using a protective strategy of mild hypothermia and sevoflurane to improve long-term neurocognitive outcome.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is part of the Topical Collection on Pediatric Anesthesia.
Rights and permissions
About this article
Cite this article
Lin, E.P., Lee, JR. & Loepke, A.W. Anesthetics and the Developing Brain: The Yin and Yang. Curr Anesthesiol Rep 5, 177–189 (2015). https://doi.org/10.1007/s40140-015-0107-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40140-015-0107-8