- Edward Capps
Although post operative psychological problems have been hypothesized in the literature for over half a century, it was not until the last few decades that the first research into the effects of anesthetics on neuronal apoptosis came into being.1 In this last decade the pace of research of the effects of anesthetics on neuronal apoptosis has skyrocketed, but as of yet no definitive answers on guidelines or strategies have been formulated1. Despite the lack of concrete answers on what, if any changes will come to the art of anesthesia from this field of research it is sure to provide an interesting subject matter for years to come.
Anatomy and Physiology
In 1999 research was performed on the effect of blockading NMDA receptors in the brains of post natal day seven rats.2 In rats post natal day seven is when peak synaptogenesis is underway, this age is used as a model for human synaptogenesis which occurs between gestational age 20-22 and continues into the infancy. 1,2 The results of NMDA antagonists on the rat brain were a marked increase in neurons undergoing apoptosis compared to the control group. 2 In addition to NMDA receptors, disrupting GABA receptors have been found capable of producing neuronal apoptosis.1
Jevtovic-Todorovic et al., tested the effects of delivering GABA inhibitory on post natal day 7 rats. In their study they used the anesthetics isoflurane, nitrous oxide, and midazolam. The group receiving isoflurane had three tiers, receiving 0.75%, 1.0%, and 1.5%. This allowed a dose dependant relationship between the amount of isoflurane used and the level of neuronal apoptosis achieved to be observed. 3 The researchers also tested the effects of combining GABA inhibitory agents with NMDA antagonists such as nitrous oxide, forming an anesthetic “cocktail.” 3 The combination of isoflurane with nitrous oxide and midazolam produced a much greater level neuronal apoptosis than isoflurane alone.3 The rats who received this combination were tested later in life to see if the effects continued on to adulthood. Their spatial memory was tested via the Morris water maze and the Radial arm maze. The anesthetic combination rats performed significantly worse than the controls, showing that the neurological deficits acquired earlier in life were still present.3
Despite the replication of these rodent studies there were concerns about the generalization of rodent studies to human physiology.1 Brambrink et al., tested the effects of isoflurane on post natal day sic rhesus macaques exposed to isoflurane for five hours. 4 Compared to the control group the experimental group had over 13 times the amount of neuronal apoptosis 3 hours post surgery.4 Another study was performed testing the effects of Ketamine in non human primates as well.4 In this study there was a significant level of neuronal apoptosis in the 24 hour infusion group of postal natal day five monkeys, however those that were only exposed to 3 hour infusions did not show any changes.5 A second primate study using ketamine was published 2 years later, again showing up to 3 hour infusions of ketamine to be safe. 6 Neuronal Apoptosis was again present in the primates exposed to the longer infusion durations of 9 hours and 24 hours.6
It is difficult to get an ideal study of human neuronal apoptosis compared to the animal models but some retrospective studies have been beneficial in looking at the possible effects related to neuronal apoptosis. DiMaggio et al., examined if an early in life hernia repair under general anesthetic would increase the rates of behavioral issues later in life. 7 In this study the cohort who underwent general anesthetic prior to the age of three were more than twice as likely to be diagnosed with a developmental diagnosis than those who did not undergo surgery.7 In a second study by DiMaggio et al., used a twin cohort to view the effects of early anesthesia on developmental disorders.8 In this study the rate of diagnoses for the exposed group was more than double the unexposed group (128.2 diagnoses versus 56.3 diagnoses per 1000 person years). 8 Wilder et al. examined the effects of anesthesia prior to age 4 on the likelihood of developing a learning disorder. 9 In this study a single exposure to anesthesia did not significantly increase the likelihood of developing a learning disorder; however multiple exposures did greatly increase occurrences of learning disabilities.9 Both the length and number of exposures had effects on the probability of developing learning disabilities later in life. 1,9
From early on in development, through birth and on into the first years of life the brain is undergoing massive amounts of synaptogenesis and the construction of neural circuits. 1, 10 At birth the human brain is only one third the size of an adult brain, however it will double in the first year of life and reach 90% of adult size by the age of 6.11 Apoptosis is a normal part of this development, synapse density peaks between 3 and 15 months of age and after that is pruned down via capsase cascades.11 NMDA antagonists and GABA agonist classes of anesthetics have all been implicated in abnormally effecting this natural process and causing excess neuronal apoptosis, particularly during peak synaptogenesis in an organism.11 The exact cause of our anesthetics effect on neuronal apoptosis is unknown, but it is known that the NMDA and GABA receptors they target mediate brain development.1,11
There are several cascades that can cause neuronal apoptosis; the two primary ones implicated in anesthetics are the mitochondrial pathway and the death receptor pathway. 1,12 The mitochondrial pathway, also known as intrinsic, is usually activated prior to the death receptor pathway, also known as the extrinsic pathway. 1 In the intrinsic pathway the downregulation of proteins results in the mitochondrial membrane becoming permeable and releases cytochrome c into the cytoplasm1 . The presence of cytochrome c in the cytoplasm triggers the caspase cascade and apoptosis1 With the extrinsic specific death receptors are triggered resulting in caspase-3 release and neuronal apoptosis1.
Isoflurane, Desflurane, and Sevoflurane are all GABA agonists and have been shown to produce apoptosis in rodents during their peak synaptogenesis periods.11 The NMDA antagonist nitrous oxide given alone has not been shown to cause apoptosis, however in combination with other drugs it has shown a synergistic effect causing more damage than the use of a single volatile anesthetic alone. 11 Studies have been conflicting on the results of benzodiazepines and neuronal apoptosis, some seem to show an effect while others do not in rodent models.11 Propofol as with the previous drugs effecting GABA has also been shown to cause significant apoptosis.11 Interestingly Dexmedetomidine by working on alpha 2 receptors rather than GABA or NMDA has not been shown to cause neuronal apoptosis, and can even protect from the damage caused by isoflurane.11,13
Even with the knowledge of what our anesthetic agents are capable of doing in animal models it may not translate the same into humans, as a result there are no hard and fast guidelines available yet.1 Miller states that the most vulnerable group is children under the age of 4 and that it is reasonable to avoid anesthesia until synaptogenesis is completed or to at least limit general anesthesia to under 2 hours if it is required.1 Since there are multiple studies showing the use of combinations of anesthetics producing a more detrimental effect there it may pay dividends to adopt a conservative “less is more” approach.14 There is current research into neuroprotective medications that can be given concomitantly with our conventional anesthetics however it is still too early to incorporate any of these techniques into practice.1,14. In their article Chiao and Zuo also agree that it is too early to change practices based on the research available, but that it may be worthwhile to delay elective surgery until after the age of four when possible.12 The recommendations found within Practice of Anesthesia for Infants and Children state that “it would be very unwise to change practice based on concerns of anesthetic neurotoxicity, while potentially increasing the risks of cardiovascular or respiratory complications.”11
Duan et al. published research on the effects of ketamine injections in combination with dexmedetomidine in rodents.15 The experiment groups were divided as follows; saline and saline, ketamine and saline, dexmedetomidine and saline, and ketamine and dexmedetomidine. They found that the administration of dexmedetomidine prevented the neuronal apoptosis that has been consistently seen with the administration of ketamine in rodents.15 Additionally they tested the subjects at 60 days of age in a Morris water maze and found that the neuroprotective effect of dexmedetomidine was long lasting.15
In the Netherlands Hansen et al. performed a retrospective analysis of educational outcomes on children who underwent pyloric stenosis repair before the age of 3 months. This study in particular is impressive because of its large enrollment, with 779 who underwent surgery and 14,665 children in the control.16 The study examined average grades scores in ninth grade and found no significant difference between the controls and the children who underwent surgery.16 This is particularly interesting because the age at which the children underwent surgery is coincides with peak synaptogensis and the age where you would expect to find the most effect of general anesthetics on neurodevlopment.1,11
One major study underway with a great chance to provide definitive information on the effects of anesthesia on pediatrics is the GAS study. This study is being completed presently with an anticipated end date of 1/07/2015. In this study 660 infants in two cohorts are compared, those undergoing general anesthesia for an inguinal hernia repair and those undergoing spinal anesthetic for the same surgery.17 By using the Wechsler Preschool and Primary Scale of Intelligence test to measure their I.Q. at 5 years of age this study should provide great insight into the affects of general anesthesia compared to regional in infants near their peak synaptogenesis.17
The occurrence of neuronal apoptosis in association with our commonly used anesthetics is an unsettling phenomenon. Unfortunately the research available is spare and sometimes provides conflicting evidence the details of process and the associations found in animal models might not extrapolate well to humans. Until more research is completed it is important for the anesthesia provider to be aware of the possibly negative side effects of our anesthetics when used during peak synaptogenesis. Despite the possibility that certain anesthetics may result in neuronal apoptosis it would be premature to change our practice. In the next few years prospective human studies will have been completed and may give us a definitive answer that we can incorporate into evidence based practices to improve patient outcomes. Once more concrete data is available we will be able to incorporate whatever risks are associated with certain anesthetics with the already known cardiovascular and respiratory factors and provide the most optimal anesthesia possible.
1. Miller RD. Miller’s Anesthesia. 8th ed. Philadelphia (PA): Elsevier; 2014: 329-345
2. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain. Science. 1999;283:70-74.
3. 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. Journal of Neuroscience. 2003;23:876-882.
4. Brambrink A. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112:834-841.
5. Slikker J, William, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicological sciences : an official journal of the Society of Toxicology. 2007;98:145-158.
6. Zou X, Patterson TA, Divine RL, et al. Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. International Journal of Developmental Neuroscience. 2009;27:727-731.
7. DiMaggio C, Sun LS, Kakavouli A, Byrne MW, Li G. 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;21:286-291.
8. DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011;113:1143-1151.
9. 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.
10. Blaylock M, Engelhardt T, Bissonnette B. Fundamentals of neuronal apoptosis relevant to pediatric anesthesia. Paediatr Anaesth. 2010;20(5):383-95.
11. Cote CJ, Lerman J, Anderson BJ. A Practice of Anesthesia for Infants and Children, Expert Consult – Online and Print. Elsevier Health Sciences; 2013.
12. Chiao S, Zuo Z. A double-edged sword: volatile anesthetic effects on the neonatal brain. Brain sciences. 2014;4:273-294.
13. Sanders R. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology. 2009;110:1077-1085.
14. Loftis, Grace Kline,C.R.N.A., M.S.N., Collins, Shawn, CRNA,PhD., D.N.P., McDowell, Mason,C.R.N.A., M.S.N.A. Anesthesia-induced neuronal apoptosis during synaptogenesis: A review of the literature.AANA J. 2012;80(4):291-8.
15. Duan X, Li Y, Zhou C, Huang L, Dong Z. Dexmedetomidine provides neuroprotection: impact on ketamine-induced neuroapoptosis in the developing rat brain. Acta Anaesthesiol Scand. 2014;58:1121-1126.
16. Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatr Anaesth. 2013;23:883-890.
17. Davidson, A. The effects of anaesthesia on neurodevelopmental outcome and apnoea in infants: the GAS study Available at: http://www.controlled-trials.com/isrctn12437565/Gas. Accessed November 15, 2014.
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