Open access peer-reviewed chapter
Noteworthy animal anesthetic risk studies.
Abstract
It is hypothesized that surgical anesthetic agents may be associated with damage to the early developing brain. There is animal evidence for anesthetic neurotoxicity, with basic science through behavioral studies demonstrating an increase in apoptosis and dendritic cell damage after exposure. However, these results have not been definitively translated to human studies. There continues to exist controversy in clinical research over whether early anesthetic exposure is associated with neurocognitive deficits, with many recent studies not supporting the theory of anesthetic drug-induced neurotoxicity in young children. There are three recent major human studies—the PANDA trial, the GAS trial, and the MASK trial—which contribute to our current perspective on anesthetic toxicity, overall suggesting that a single exposure for a healthy individual may be safe, but multiple exposures may have risk. Every surgery should contain a risk-benefit analysis to determine whether the advantages of an early procedure during a developmental phase justifies a potential neurotoxicity from the utilized anesthetics. We may need to re-evaluate the timing and number of stages of surgeries in our treatment protocols to account for these risks.
Keywords
- neonatal
- anesthesia
- neurotoxicity
- cognitive
- neurodevelopment
1. Introduction
Millions of children worldwide each year undergo surgical, diagnostic, and therapeutic procedures that require pediatric anesthesia care. The only way that these can be safely done is by the implementation of safe and effective anesthesia practices. In our field of craniofacial surgery, the habilitation of children is only possible due to reliably safe and effective general anesthesia. Nevertheless, there persists concern that the administration of apparently uncomplicated general anesthetic in an otherwise healthy child, which is often readily used in adults, could lead to later neurocognitive deficits. A significant amount of research has gone into exploring these concerns; however, the clinical significance of anesthetic neurotoxicity remains uncertain. It is incumbent on cleft and craniofacial surgeons, who commonly operate on infants during the neurocognitive developmental years, to strive for safety and lead this conversation.
Cleft and craniofacial surgeons are responsible for the care of children with craniofacial differences who require multiple staged procedures in their early childhood, and, thus, must assess whether the benefits of these procedures justify a potential, immeasurable anesthetic risk. We may need to re-evaluate the timing and number of stages of surgeries in our treatment protocols to account for these risks. An added pressure arises from the fact that this issue is discussed in the popular media, and worried parents may bring this as a concern to their surgical team. The evidence from animal studies for anesthetic neurotoxicity is concerning; however, larger human studies have conflictingly found less effect of anesthetic on neurocognitive development.
2. Animal studies
Animal research for the past decade has supported the hypothesis that the use of anesthetic agents during periods of rapid brain development, such as the neonatal years, are associated with increases in dendritic cell damage and neuroapoptosis in the central nervous system [1, 2, 3, 4, 5, 6, 7]. There have been a substantial number of articles implicating deficits in learning, memory and behavior in non-human species, particularly rats and primates [8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]. Unfortunately, many commonly used anesthetic agents, including propofol, midazolam, and sevoflurane, have been implicated in neurocognitive development concerns.
Mechanistically, anesthetics tend to work on GABA and NMDA receptors. For instance, propofol and sevoflurane bind to GABA-A receptors to enhance inhibitory GABA effects. Sevoflurane and ketamine antagonize NMDA receptors. The agents’ involvement in these and other pathways may incidentally cause cognitive impairment. For instance, sevoflurane has been implicated in the ubiquitination-proteasome pathway [10]. Increasing doses of propofol, midazolam, isoflurane, and ketamine have all been associated with activating caspase-3, which is a marker of neuroapoptosis. Gene expression, using RNA sequencing, is also impacted following multiple anesthetic exposures. Studies have isolated specific neural locations and cell types affected by anesthetic exposure, finding the hippocampus, anterior thalamic nuclei, mammillary bodies, retrosplenial cortex, and oligodendrocytes to be particularly susceptible [6]. Table 1 summarizes findings from recent animal studies.
| Study | Year | Model | Outcome measures | Findings |
|---|---|---|---|---|
| Song et al. | 2019 | Mouse | ABGs, behavioral studies, and RNA sequencing | There are differentially expressed genes in the hippocampus following multiple anesthetic exposures, inducing social behavior disorders. |
| Cattano et al. | 2008 | Mouse | Quantitative activated caspase-3 levels following propofol exposure | Propofol triggers neuroapoptosis in the developing mouse brain. |
| Brambrink et al. | 2010 | Rhesus monkey | Quantitative activated caspase 3-stained neurons following isoflurane exposure | Exposing infant rhesus macaques to five hours of anesthetic is associated with a 13-fold increased rate of neuroapoptosis. |
| Brambrink et al. | 2012 | Rhesus monkey | Location of apoptosis within the brain following exposure | Oligodendrocytes were selectively vulnerable for apoptosis following anesthetic exposure in infant rhesus macaques. |
| Jevtovic-Todorovic et al. | 2003 | Rat | ABGs, activated caspase-3 levels, electrophysiological studies, behavioral studies | Exposure to anesthesia resulted in lasting deficits in hippocampal, anterior thalamic nuclei, mammillary bodies, and retrosplenial cortex synaptic function, mediated by GABA and NDMA |
| Creeley et al. | 2013 | Rhesus monkey | Activated caspase-3 levels as a measure of apoptotic degeneration | Five hours of propofol exposure was associated with neuronal and oligodendrocyte apoptosis. |
| Coleman et al. | 2017 | Rhesus monkey | Behavioral studies | Following multiple isoflurane exposures, monkeys had reflex deficits and increased anxiety. This was not seen after single exposure. |
| Raper et al. | 2015, 2018 | Rhesus monkey | Behavioral studies | Following multiple sevoflurane exposures, monkeys had a higher frequency of anxiety-related behaviors and emotional reactivity. |
Table 1.
These well-documented findings serve as the source for significant concern when translating the potential neurocognitive effects of early anesthetic exposure to human patients.
3. Human studies
On the other hand, studies in humans are less clear regarding neonatal toxicity. In comparison to animal studies, human studies are obviously limited by ethical considerations. There are three recent, major prospective human trials on pediatric anesthesia. The Pediatric Anesthesia & Neurodevelopment Assessment (PANDA) trial was a large, multi-center, sibling-matched cohort study from Columbia University conducted between 2009 and 2015 [19]. They compared healthy siblings where one had a single anesthesia exposure during an inguinal hernia surgery prior to the age of three, and the other did not. The primary outcome of intelligence quotient (IQ) and secondary cognitive assessments were evaluated years later, between participant ages of eight and fifteen, to allow time for neurocognitive development. The study found no significant difference in IQ between the two siblings. They also did not find any statistically significant differences in secondary outcomes, including memory, attention, visuospatial function, adaptive behavior, executive function, and verbal fluency. Limitations of this study include lack of analysis on repeated neonatal anesthesia exposure and female participants.
The general anesthesia vs. awake-regional anesthesia (GAS) study recruited infants from 2007 to 2013 as an international collaboration of institutions from Australia, the United States, Canada, Italy, the United Kingdom, New Zealand, and the Netherlands [20]. The investigators performed an assessor-blinded, randomized control clinical trial on infants under 60 weeks old who were born after 26 weeks of gestation and scheduled to undergo inguinal hernia repair. The participants were randomly assigned to receive either general anesthesia with sevoflurane or regional spinal anesthesia with bupivacaine or levobupivacaine. Five year follow ups were performed with the Wechsler Preschool and Primary Scale of Intelligence Full Scale Intelligence Quotient (WPPSI-III FSIQ) as a measure of neurocognitive function. They found that, following the median duration of about 1 hour of anesthesia exposure in the first 60 weeks of life, there were no significant difference in IQ and neurodevelopmental outcomes in children after 5 years. Similarly to the prior study, the GAS study was limited by its lack of analysis on female children and children with repeated anesthesia exposures.
Finally, the Mayo Anesthesia Safety in Kids (MASK) trial from the Mayo Clinic recruited children who were unexposed, singly exposed, or multiply exposed to anesthesia prior to the age of three between 1994 and 2007 [21]. They then used the Wechsler Abbreviated Scale of Intelligence (WASI) scale to evaluate IQ and other measures of neurocognitive development between the ages of 8–12 and 15–20. They found that any amount of exposure to anesthesia did not have an association with significant differences of IQ as the primary outcome. However, multiple anesthesia exposures may be associated with reduction of secondary outcomes of processing speed, fine motor coordination, and parent reported difficulties with behavior and reading. A strength of this study is its evaluation of the effect of repeated exposures; however, limitations include an inability to account for inherent differences that may result in patients requiring multiple early procedures, varied anesthetic types, and an uncontrolled variable of half of the participants having anesthetic exposure after the age of three (Table 2).
| Study | Publication year | Recruitment location | Study size | Findings |
|---|---|---|---|---|
| PANDA | 2016 | USA | 105 paired siblings | Following a single anesthetic exposure, there was no significant difference in IQ, memory, attention, visuospatial function, adaptive behavior, executive function, and verbal fluency between two siblings. |
| GAS | 2019 | Australia, Italy, USA, UK, Canada, Netherlands, and New Zealand | 205 children with regional anesthetic vs. 242 general | Following a median of one 1 of single anesthetic exposure in the first 60 weeks of life, there were no significant difference in IQ or neurocognitive development outcomes in children. |
| MASK | 2018 | USA | 997 children | Any amount of exposure to anesthesia (single or repeated) was not associated with IQ differences. However, multiple exposures may be associated with reduction of processing speed, fine motor coordination, and parent reported difficulties with behavior and reading. |
Table 2.
Noteworthy human anesthetic risk trials.
There are numerous smaller human studies that have corroborated the theory that neonatal anesthesia has minimal effects on neurocognitive development [22, 23]. However, the data is mixed. The current findings remain contradictory, with some evidence also suggesting that there may exist small differences in neurocognitive development that remain critical to be explored [3, 24, 25]. Additionally, along with the MASK trial, there are other studies supporting the theory that repeated exposure may be associated with worse long-term cognitive outcomes [26, 27, 28].
4. Application to neonatal surgery
The above human studies focused on otherwise healthy children with surgeries that do not necessarily reflect an underlying condition that may complicate the neurocognitive development. Children born with cleft lips and palate provide an interesting population of relatively healthy children that typically require multiple exposures to anesthesia at a young age.
Pediatric craniofacial surgeons typically treat children with cleft lip and cleft palate using treatment protocols that require at least two surgeries, or multiple anesthetic exposures, during infancy. There is critical evidence supporting the theory that these surgeries are time-sensitive; specifically, palate repair will provide a superior speech outcome if it is performed before the critical period of language acquisition. There are decades of level III evidence case series that address this argument. In 1982, Dorf and Curtin found that children who received a palate repair after the age of 1 year had a 90% incidence of compensatory articulations, whereas those who had the repair prior to the 12 months of age had a less than 5% incidence of compensatory articulations [29]. A similar finding was discovered by Chapman and Hardin in the same year of a 90% incidence of compensatory articulations for late palate repairs [30].
In 2000, Kirschner et al. compared children undergoing Furlow palatoplasties prior to 7 months of age and after, and they found no significant difference in speech scores, velopharyngeal incompetence, and rate of secondary pharyngoplasty [31]. In 2008, Chapman et al. compared lexical outcomes in a level II multicenter prospective series for children undergoing palatal surgery. They discovered that those operated on under the age of 11 months with less preoperative lexical ability ultimately had better speech outcomes than those with better preoperative lexical ability with their surgery at a mean age of 15 months [32]. There are additional recent studies supporting equivalent or superior outcomes for cleft lip repair in children younger than 3 months of age [33, 34]. All these studies show that there may be lexical benefits to early operative intervention that must be weighed against the theoretical risk of early anesthetic exposure.
The Timing for Primary Surgery (TOPS) trial, recently published in 2023, is a multicenter, randomized controlled trial conducted across Brazil, Denmark, Norway, Sweden, and the UK [35]. Infants were assigned to receive surgery at either 6 months or 12 months of age. They found that those with earlier surgeries had significantly lower incidence of velopharyngeal insufficiency by 5 years of age. At 1 year old, canonical babbling, hearing sensitivity, and middle-ear function were better in children with earlier repair, however this difference became insignificant by 5 years of age. Notably, early repair was more significantly associated with maxillary arch constriction, though other technical outcomes were similar. These findings across the above studies may indicate persuasive support for early operative intervention, which should be weighed against potential risks.
Craniofacial surgeons also frequently refer children for perioperative diagnostic imaging procedures that require anesthesia. The same trepidations applied to surgical anesthesia exposure risk should be considered for diagnostic and planning imaging studies on young children, who often circumstantially require general anesthesia to complete required studies. Is there a theoretical benefit to limiting the number of preoperative studies or operative stages to deliver a comparative effective care while minimizing risks? There are few studies that explore this. Conrad et al. retrospectively reviewed children with cleft palates and found no association between number of surgeries and academic ability but did find a negative association with social involvement [36]. Clausen et al. compared academic scores of children with cleft lip or cleft palate or both, and found that cleft type affected academic outcomes, but number of surgeries did not, though they acknowledged that this latter finding was limited and ambiguous [37].
While we continue to research for more definitive answers to this dilemma, neonatal and pediatric surgeons should familiarize themselves with this issue and develop answers to questions from parents seeking reassurance and better understanding. Some pediatric surgeries (including lower extremity procedures, inguinal hernia repairs, circumcision, etc.) can be safely and efficiently conducted under a regional anesthetic technique such as spinal anesthesia with much less presumed neurocognitive risk. Multiple studies have shown that spinal anesthesia is effective and safe with respect to neurological risk and should be explored if appropriate [38, 39, 40]. However, this is not necessarily possible with all surgeries, particularly cleft and craniofacial procedures. These surgeries and the required anesthesia for a safe operation should not be withheld from children in need.
The clear next question is, if we accept that there may be an anesthetic neurocognitive risk for young children, particularly in the incidence of multiple exposures, what can be done to mitigate this effect on our cleft and craniofacial patients who cannot rely on spinal or local anesthesia due to the location of the operation? Shorter operations may mitigate risk, so surgical technique could be modified to prioritize brevity of anesthetic exposure. Postoperatively, patients may benefit from focused developmental training in implicated cognitive fields, including fine motor coordination, behavior, and reading. Further research should be done on molecular and animal models to compare the different anesthetics and determine if certain agents have less neurodegenerative impact. One recent study associated propofol specifically with less effect on neurocognition [41]. There is certainly room for more exploration of this field.
5. Conclusion
Currently, the evidence for neonatal anesthetic toxicity is not yet definitive on whether recommendations should be made regarding age at or number of procedures. Certainly, multiple large studies seem to suggest that it may be safe to perform anesthesia on infants in the neurodevelopmental period; however, there does seem to be a contradiction between human and animal models [42]. The surgeon must weigh a recommendation to delay or limit these procedures against the benefits of early surgical repair. In the field of craniofacial surgery, could there be a reduced risk of neurocognitive toxicity by changing a surgical protocol to one of shorter, later, or fewer staged repairs, or would that too significantly imbalance the scale toward poorer patient outcomes? [43] Could patients at risk benefit from focused neurodevelopmental training postoperatively? Potential risks and benefits should continue to be investigated to promote the long-term safety of our young patient population. Surgeons of all surgical subspecialties should be aware of the concerns of anesthesiologists, pediatricians, and the public regarding potential neurotoxicity of general anesthetics, and they should be cognizant of the limitations of the current evidence.
Conflict of interest
The authors declare no conflict of interest.
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