In 2016, the U.S. Food and Drug Administration issued a warning that general anesthesia may affect brain development in children. This was particularly true for procedures lasting more than 3 hours or multiple procedures in children younger than 3 years.1 Although helpful to pediatric ophthalmologists in guiding the timing of elective cases, such as strabismus surgery, diagnoses such as trauma, congenital cataract, and congenital glaucoma may require urgent surgery and early anesthetic exposure. Knowledge of the recent publications regarding the neurodevelopmental outcomes of early general anesthesia exposure is important in guiding both patient care and parent education. To this point, dedicated education programs have been put into place in some health care systems that include a discussion with the parents, surgeons, and anesthesiologists regarding the duration of anesthesia, planning for multiple general anesthetic events, and the possibility of delaying procedures.2,3
The initial data on the neurotoxic effects of general anesthesia originated from animal studies. Most of these studies focused on neuronal apoptosis as a marker of anesthetic toxicity. Apoptosis is an important physiologic process that occurs during all stages of development. Its role is to eliminate neurons that are redundant, fail to complete migration, do not mature properly, or connect inappropriately with other neurons. The concern for the neurotoxicity of anesthetic agents arose when studies demonstrated higher rates of dysregulated apoptosis than in age-matched animal controls with either placebo or no anesthesia exposure.4
Several studies investigated the effects of commonly used anesthetics, including sevoflurane and ketamine, and found significant anatomic effects, particularly in the hippocampus. It has been demonstrated in rats exposed to 3% sevoflurane for a 4-hour duration that there were increased connexin 43 levels in the hippocampus of 7-day-old rats (the equivalent of a human younger than 1 year), which is associated with neuroapoptosis.5 A single ketamine exposure at postnatal day 7 in rats led to a short-term reduction in the hippocampal cellular viability and long-term alterations in hippocampal glutamate transport.6 Another study suggested that exposure to ketamine in 7-day-old rats induced mitochondrial fission, leading to excessive free radical formation and metabolic disturbances, and subsequently neurotoxicity.7 A study by Woodward et al.8 showed that these effects are potentially permanent, because exposure to isoflurane and nitrous oxide for 6 hours at postnatal day 7 caused lasting alterations in synaptic transmission and neuronal excitability. Additionally, the period of vulnerability to general anesthetics may be longer than early childhood, as initially thought. Landin et al.9 demonstrated that isoflurane exposure within a well-characterized adolescent period in rats elicited immediate and persistent anxiety responses, as well as delayed cognitive impairment into adulthood. Overall, the studies suggest that neurotoxic changes in rat brains occur due to anesthetic exposure in early development.
Studies have been performed in non-human primates given their close resemblance to humans. Brambrink et al.10 found that rhesus macaque monkeys who underwent 5 hours of exposure to isoflurane at 6 days of age had a 13-fold increase in acute apoptotic neurodegeneration when compared to age-matched controls. This occurred not only in the cerebral cortex, but also in the gray matter throughout the brain. Other authors found that even shorter exposures to general anesthesia in infant monkeys resulted in similar changes, although to a lesser degree. One study found that 3 hours of exposure to isoflurane in monkeys resulted in a fourfold increase in neuronal and oligodendroglia apoptosis compared to controls.11 This was supported by a study by Slikker et al.,12 who demonstrated that ketamine administered to rhesus monkeys intravenously for 24 hours produced a significant increase in the number of apoptotic and necrotic neurons in the cortex of 5-day-old monkeys. However, the same effects were not seen in 35-day-old monkeys.
A few studies have examined how the physiologic changes translate into behavior and cognitive effects. In rhesus monkeys exposed to sevoflurane during the first month of life, there was a higher frequency of anxiety-related behaviors than in control monkeys.13 This finding was supported by Coleman et al.,14 who compared the motor behavior and anxiety levels between monkeys with a single 5-hour exposure of isoflurane and three similar length exposures to isoflurane. The authors found deficits in motor reflexes at 1 month of age and increased levels of anxiety and appeasement behavior at 12 months of age in the monkeys with multiple, but not isolated, exposure when compared to unexposed monkeys. These studies confirm the finding that early exposure to anesthesia, particularly repeat episodes, may have long-term motor and socioemotional consequences in primates.
There are several limitations to animal data beyond the complexity of the neural circuitry. First, the studies rely on healthy animals, whereas children undergoing anesthesia may have clinical diagnoses that render them less healthy than age-matched controls. Additionally, postoperative inflammatory and proinflammatory cytokines may also play a role in apoptosis. Postoperative pain may also affect outcomes, because pain can be associated with multiple complications in and of itself. Several recent studies aim to supplement the knowledge gap from animal studies.
Laboratory studies have produced conflicting results on the neurotoxicity of anesthetic agents on neural substrates. One study investigating the effect of a single-episode neonatal exposure to sevoflurane on the microRNA expression in the adult human brain showed significant changes in the pathways relating to neuronal development, such as focal adhesion, axon guidance, and actin cytoskeleton.15 This was supported in a study by Zhou et al.,16 in which the authors found that exposure of neural stem cells to sevoflurane resulted in decreased cell density and viability. In contrast, Park et al.17 did not find corollary changes in the brain when investigating the effects of short-term exposure to various concentrations of sevoflurane on neural precursor cells derived from human embryonic stem cells. The authors found that there were short-term effects after 2 hours of exposure with 6% sevoflurane that did not persist, and there were no effects on cell proliferation at any of the concentrations. Therefore, they concluded that 2 hours of sevoflurane exposure produced no significant changes in the survival, proliferation, apoptosis, and differentiation of human neural precursor cells. These conflicting results indicate there is still a great deal to be learned in regard to the cellular effects of anesthetic agents in infants and children.
To produce high-quality, clinically relevant data on anesthetic neurotoxicity, the U.S. Food and Drug Administration and the International Anesthesia Research Society developed a public-private partnership called SmartTots or “Strategies for Mitigating Anesthesia-Related Neuro-Toxicity in Tots.”18 The program studied the safety of anesthesia in infants and children with a focus on randomized, prospective trials. The main studies include the General Anesthesia and Apoptosis (GAS), the Pediatric Anesthesia Neuro Development Assessment (PANDA), and the Mayo Safety in Kids (MASK) projects. All three of these projects used full-scale intelligence quotient (FSIQ) of the Weschler Abbreviated Scale of Intelligence (WASI) as the primary outcome measure. The secondary outcomes also included prospective neurocognitive and behavioral testing.
The GAS was a prospective, multicenter, randomized controlled study that monitored neuro-cognitive development in neonates who underwent herniorrhaphy at 420 days' postmenstrual age or less. Patients from 28 centers in seven countries were randomly assigned to receive either general anesthesia using sevoflurane or regional anesthesia using bupivacaine or levobupivacaine. Mean post-menstrual age at exposure was 317.2 ± 31.9 days for the awake regional anesthesia group and 319.7 ± 31.8 days for the general anesthesia group. Five-year outcomes data were obtained for 205 children in the awake regional anesthesia group and 242 children in the general anesthesia group. The 2-year data showed evidence of equivalence in cognitive composite scores (difference in means = 0.169 [95% confidence interval [CI]: −2.30 to 2.64]).19 Likewise, the 5-year data reflected equivalence in mean FSIQ scores between the two groups (difference in means = 0.23 [95% CI: −2.59 to 3.06]).20 The 5-year data also showed equivalence in verbal, performance, and processing composite scores, as well as caregiver-reported outcomes. It should be noted that all exposures to general anesthesia were shorter than 120 minutes.
The PANDA was a multicenter study that compared patients who underwent herniorrhaphy using general anesthesia prior to 3 years of age to an un-exposed sibling. The authors retrospectively identified 105 sibling pairs and performed prospective neurocognitive testing at ages 8 to 15 years. All exposed children received inhaled agents (sevoflurane, isoflurane, or both). Twenty-eight children received intravenous agents (propofol, thiopental, ketamine, and midazolam), 75 received opioids, and 39 received adjuvant caudal anesthesia. Additionally, 33 children received midazolam for preoperative anxiolysis. The mean age at exposure was 17.3 ± 10.9 months. The mean age at testing was 10.6 ± 2.0 years for the exposed siblings and 10.9 ± 1.7 years for the unexposed siblings. Exposure time ranged from 20 to 240 minutes. The differences in mean values for FSIQ, performance intelligence quotient, and verbal intelligence quotient were −0.2 (95% CI: −2.6 to 2.9), 0.5 (95% CI: −2.7 to 3.7), and 0.5 (95% CI: −3.2 to 2.2), respectively. Therefore, the study found no statistically significant differences between siblings in the primary outcome measures. There were also no statistically significant differences between siblings for mean scores of neurocognitive tests for memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. The authors concluded that there is no effect of a single anesthesia exposure prior to age 36 months on neurocognitive function or behavior. It should be noted that the PANDA study does not account for exposure to anesthesia following age 36 months in either the study group or their unexposed siblings.21
The MASK study compared neurocognitive and behavioral outcomes between children who received zero, one, or multiple exposures to general anesthesia using sevoflurane before 3 years of age. Patients were identified retrospectively and underwent prospective neuropsychological testing in two age cohorts, preadolescent (age 8 to 12 years) and adolescent (age 15 to 19 years). The mean gestational ages at the time of exposure for patients with zero, one, and multiple exposures were 38.7 ± 2.4, 38.6 ± 2.4, and 38.2 ± 2.8 weeks, respectively. The authors found no differences between groups in the primary outcome measure (FSIQ). Additionally, there were no differences identified between age groups. The authors did identify modest deficits in executive function scores in children with multiple exposures but not children with a single exposure compared to unexposed patients. Multiple exposures were associated with decreased scores in reading and verbal code retrieval (mean difference of −3.5 [95% CI: −6.3 to −0.7], P = .014) and fine motor skills (mean difference = −5.5 [95% CI: −8.4 to 2.6], P < .001) compared to unexposed children.22 A secondary analysis of the MASK study using factor analysis found an association between multiple exposures and deficits in a factor reflecting motor skills, visual-motor integration, and processing speed (mean difference = −0.35 [95% CI: −0.57 to −0.13], P = .002). A cluster analysis grouped children into three groups based on overall performance on most tests. Children with multiple exposures to general anesthesia were 2.85 times more likely to belong to the lowest scoring group than to the middle group (95% CI: 1.49 to 5.35, P = .002). Despite this result, it is important to note that a majority of children with multiple exposures belonged to the two higher scoring groups. The authors of the MASK study could therefore not rule out an association between multiple anesthesia exposures and fine motor skills or other neurocognitive deficits.22
To minimize the toxicity of general anesthesia, delaying the procedure may be considered. However, avoiding anesthesia is not practical in most cases, particularly for congenital cataracts and/or glaucoma. Fortunately, there are studies investigating alternatives to minimize the potential side effects, including newer agents and the addition of protective agents to the anesthetic mix.
Animal studies have shown the neuroprotective effects of various adjuvant treatments alongside common anesthetics. These agents have been shown to decrease neuroinflammatory and neuroapoptosis pathways caused by general anesthetic drugs. Shi et al.23 showed that pretreatment with hydrogen gas attenuated the excitation of the NF-kB pathway and subsequent proinflammatory cytokine release caused by sevoflurane in neonatal rats. Dexmedetomidine reduced overactivation of neuronal excitatory pathways caused by both sevoflurane and isoflurane.24,25 Joksimovic et al.26 showed that histone deacetylase inhibitor entinostat reduced epigenetic neuronal overexcitation and thus limited the alterations in the inhibitory synaptic transmission due to anesthesia with isoflurane and nitrous oxide in 7-day-old rats.
Some authors have shown neuroprotective effects more directly linked to learning and memory pathways in animal models. One study used the nitric oxide donor molsidomine to prevent long-term potentiation changes in axons and acute memory impairment in mouse models. Mice treated with nitric oxide showed better discrimination between known and unknown objects 2 weeks after exposure than mice treated with isoflurane alone.27 Ding et al.28 treated mice exposed to sevoflurane with epigallocatechin-3-gallate, a polyphenol found in green tea. They showed reduced neuroapoptosis and increased activity of multiple cellular pathways involved in memory retention and learning as compared to sevoflurane alone. Finally, Giri et al.29 showed that pretreatment of rat pups with minocycline prior to midazolam exposure increased hippocampal cell proliferation compared to midazolam alone. The pretreated rats showed better cognitive function, spatial learning, and memory abilities at 35 days after exposure than those solely exposed to midazolam. Of note, none of the studies investigated the outcomes more than 3 months after exposure.
Overall, the neurotoxicity of general anesthetics in animal studies does not seem to have a direct correlation to adverse neurodevelopmental outcomes in human studies. Although prospective human studies do not demonstrate intelligence quotient differences in children exposed to anesthesia, the MASK study suggests a possible, modest negative impact in executive function associated with multiple anesthetic exposures prior to the age of 3 years. Thus, whenever feasible, pediatric eye surgeons should make an effort to minimize the number of anesthetic episodes required in these patients. New studies are investigating the role of adjuvant therapies to minimize the neurotoxicty of general anesthetics; however, there are no recent studies that have explored the long-term neurological effects of adjuvant agents in humans. Future studies will provide greater insight into the safety and utility of these agents.
- United States Food and Drug Administration. FDA drug safety communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm. Accessed May 31, 2019.
- Andropoulos DB, Greene MF. Anesthesia and developing brains: implications of the FDA warning. N Engl J Med. 2017;376(10):905–907. doi:10.1056/NEJMp1700196 [CrossRef]28177852
- Olutoye OA, Baker BW, Belfort MA, Olutoye OO. Food and Drug Administration warning on anesthesia and brain development: implications for obstetric and fetal surgery. Am J Obstet Gynecol. 2018;218(1):98–102. doi:10.1016/j.ajog.2017.08.107 [CrossRef]
- Jevtovic-Todorovic V. Exposure of developing brain to general anesthesia: what is the animal evidence?Anesthesiology. 2018;128(4):832–839. doi:10.1097/ALN.0000000000002047 [CrossRef]
- Bi C, Cai Q, Shan Y, et al. Sevoflurane induces neurotoxicity in the developing rat hippocampus by upregulating connexin 43 via the JNK/c-Jun/AP-1 pathway. Biomed Pharmacother. 2018;108:1469–1476. doi:10.1016/j.biopha.2018.09.111 [CrossRef]30372849
- Sampaio TB, de Oliveira LF, Constantino LC, et al. Long-term neurobehavioral consequences of a single ketamine neonatal exposure in rats: effects on cellular viability and glutamate transport in frontal cortex and hippocampus. Neurotox Res. 2018;34(3):649–659. doi:10.1007/s12640-018-9927-x [CrossRef]29968149
- Eustaquio T, Wang C, Dugard CK, et al. Electron microscopy techniques employed to explore mitochondrial defects in the developing rat brain following ketamine treatment. Exp Cell Res. 2018;373(1–2):164–170. doi:10.1016/j.yexcr.2018.10.009 [CrossRef]30342004
- Woodward TJ, Timic Stamenic T, Todorovic SM. Neonatal general anesthesia causes lasting alterations in excitatory and inhibitory synaptic transmission in the ventrobasal thalamus of adolescent female rats. Neurobiol Dis. 2019;127:472–481. doi:10.1016/j.nbd.2019.01.016 [CrossRef]30825640
- Landin JD, Palac M, Carter JM, et al. General anesthetic exposure in adolescent rats causes persistent maladaptations in cognitive and affective behaviors and neuroplasticity. Neuropharmacology. 2019;150:153–163. doi:10.1016/j.neuropharm.2019.03.022 [CrossRef]30926450
- Brambrink AM, Back SA, Riddle A, et al. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72(4):525–535. doi:10.1002/ana.23652 [CrossRef]23109147
- Noguchi KK, Johnson SA, Dissen GA, et al. Isoflurane exposure for three hours triggers apoptotic cell death in neonatal macaque brain. Br J Anaesth. 2017;119(3):524–531. doi:10.1093/bja/aex123 [CrossRef]28969320
- Slikker W Jr, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98(1):145–158. doi:10.1093/toxsci/kfm084 [CrossRef]17426105
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- Coleman K, Robertson ND, Dissen GA, et al. Isoflurane anesthesia has long-term consequences on motor and behavioral development in infant rhesus macaques. Anesthesiology. 2017;126(1):74–84. doi:10.1097/ALN.0000000000001383 [CrossRef]
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- Zhou X, Lu D, Li WD, et al. Sevoflurane affects oxidative stress and alters apoptosis status in children and cultured neural stem cells. Neurotox Res. 2018;33(4):790–800. doi:10.1007/s12640-017-9827-5 [CrossRef]
- Park JW, Lim MS, Ji SY, et al. Effects of short-term exposure to sevoflurane on the survival, proliferation, apoptosis, and differentiation of neural precursor cells derived from human embryonic stem cells. J Anesth. 2017;31(6):821–828. doi:10.1007/s00540-017-2408-1 [CrossRef]28913662
- Smart Tots Consensus Statement Supplement 11/2015. http://smarttots.org/consensus-statement-supplement/. Accessed April 19, 2019.
- Davidson AJ, Disma N, de Graaff JC, et al. GAS Consortium. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016;387(10015):239–250. doi:10.1016/S0140-6736(15)00608-X [CrossRef]
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- Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: the Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018;129(1):89–105. doi:10.1097/ALN.0000000000002232 [CrossRef]29672337
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- Shi Y, Wang G, Li J, Yu W. Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor κ-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats. Neuroreport. 2017;28(17):1170–1175. doi:10.1097/WNR.0000000000000899 [CrossRef]28926473
- Shan Y, Yang F, Tang Z, et al. Dexmedetomidine ameliorates the neurotoxicity of sevoflurane on the immature brain through the BMP/SMAD signaling pathway. Front Neurosci. 2018;12:964. doi:10.3389/fnins.2018.00964 [CrossRef]
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- Joksimovic SM, Osuru HP, Oklopcic A, Beenhakker MP, Jevtovic-Todorovic V, Todorovic SM. Histone deacetylase inhibitor entinostat (MS-275) restores anesthesia-induced alteration of inhibitory synaptic transmission in the developing rat hippocampus. Mol Neurobiol. 2018;55(1):222–228. doi:10.1007/s12035-017-0735-8 [CrossRef]
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- Ding ML, Ma H, Man YG, Lv HY. Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can J Physiol Pharmacol. 2017;95(12):1396–1405. doi:10.1139/cjpp-2016-0333 [CrossRef]28679060
- Giri PK, Lu Y, Lei S, et al. Pretreatment with minocycline improves neurogenesis and behavior performance after midazolam exposure in neonatal rats. Neuroreport. 2018;29(3):153–159. doi:10.1097/WNR.0000000000000937 [CrossRef]