January 7, 2020
by Gino Gizzarelli, BScPhm, DDS, MSc (Dental Anaesthesia)
Every day children of all ages are sedated or anaesthetized for dental treatment both in the hospital and more commonly now in the dental office. The use of physical restraint for a dental procedure in a child has largely been replaced or significantly reduced with the use of sedative or general anaesthetic drugs.
Previously it was thought that there may be a link between major surgery in the neonate and an increased risk of neurodevelopmental problems. Anaesthesia, at the time, was not considered as a cause for this association.1
A landmark study by Wilder from the Mayo Clinic in Minnesota was published in 2009. This was a population based, retrospective birth cohort study. The educational and medical records of approximately 5,300 children born to mothers residing in a small city in Minnesota from 1976 to 1982 were reviewed to identify children with learning disabilities. This rather homogeneous population of kids were followed for 19 years. Of the 5,357 children, 593 received anaesthesia before the age of four. Compared with those not receiving anaesthesia, 449 kids received a single exposure to anaesthesia and this was not associated with an increased risk of learning disability. However, those kids that received two anaesthetics (100 kids) and those that received three or more anaesthetics (44 kids) were at an increased for learning disabilities. In addition, this study demonstrated an increased risk of learning disabilities with longer duration of anaesthesia exposure. The conclusion of the study was that anaesthesia was a risk factor for the later development of learning disabilities in children receiving multiple but not single anaesthetics. The other conclusion was that it was unknown whether anaesthesia itself may contribute to learning disabilities or whether there are other unidentified factors that can contribute to learning disabilities.2 One of the problems with this study was that the children were born between 1976 and 1982 and 593 of them received anaesthesia before the age of four. Pulse oximetry, a very valuable and integral measure of the oxygenation of the patient was not commercialized until 1980 and it did not become the standard of care in anaesthesia monitoring until 1987. With the lack of pulse oximetry, it is possible that hypoxia or subclinical hypoxia was difficult to detect by looking at the colour of the child alone.
Over the last decade, a great deal of research has been dedicated to the effect of general anaesthetic drugs on the brain in particular, on the developing brain. Preclinical laboratory experiments, both in vivo and in vitro, have found that anaesthetic agents have significant neurotoxic potential.3 These studies have shown that not only neurons undergo extensive apoptotic damage (cell death), but also glial cells such oligodendrocytes are affected. Oligodendrocytes are necessary for myelination of axons. Therefore, early anaesthetic exposure could lead to cognitive impairment and negatively impact neurobehavioural development as well.3
Isoflurane (a general anaesthetic vapour drug), propofol (a common intravenous sedative/anaesthetic drug) and ketamine (another intravenous sedative/general anaesthetic commonly used in hospital emergency departments) have been shown to impair axon and dendrite formation in mice.3 A greater proportion of preclinical studies have found abnormalities with progressively longer exposures of laboratory animals to anaesthetic drugs.3 A six-hour exposure to a mixture of nitrous oxide, isoflurane and midazolam induced long term learning deficits in post-natal rats. Early exposure to routine general anaesthetics with isoflurane, propofol and ketamine are capable of producing long lasting cognitive behavioural and memory deficiency in rodents when exposed early in the post-natal period. Studies in non-human primates had similar results. There was a persistent decline in cognitive, executive, memory and motivation-based tasks.4 The vast majority of studies were done in young animals but there is no evidence to suggest these abnormalities are absent in older animals. In addition to functional defects in memory and learning, studies have also shown defects in behaviour in non-human primates.1
Although brain structure and function develop throughout childhood, a period of peak synaptogenesis in early childhood has strong implications for later cognition, language and social behaviour. Exposure during this “vulnerable time window” of brain development ought to be the focus of anaesthetic research.5 The timing is perhaps better defined in animal species. In humans, studies have defined this time period as being from the third trimester of pregnancy up to the age of three. This may be an oversimplification since there is significant variability but it seems to be the most practical time period to investigate the effects of anaesthetic exposure in humans.5
The evidence regarding the effects of anaesthesia on the developing brain prompted the U. S. Food and Drug Administration (FDA) in 2017 to issue a warning regarding the use of sedative drugs and anaesthetic agents. It reads as follows:6
The U.S. Food and Drug Administration (FDA) is notifying the public that we have approved previously announced label changes regarding the use of general anesthetic and sedation medicines in children younger than three years. These changes include:
This warning has been applied to the following 11 sedative and general anaesthesia drugs:
This list includes anesthetic and sedation drugs that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity. No specific medications have been shown to be safer than any other.
This warning suggests that brief exposure is likely safe. Luckily, only a small proportion of children require anaesthesia for dental procedures prior to the age of three, simply because eruption of the primary dentition is not complete until 25 to 33 months.
Extrapolating preclinical data from laboratory animals and applying it to humans is extremely difficult. It is impossible to design a study in humans that could confirm or rule out an effect of anaesthesia on neurodevelopment.1 In reviewing the literature, there are a number of studies whose results and conclusions differ from those of Wilder in 2009. When reviewing any study determining possible cause and effect, special attention is given to the size or power of the study, study design, the time period and the ability to control for confounding factors.
Academic performance or school grades can be relatively easily extracted from existing databases. They are important outcomes but they are not perfect in assessing some areas of neurodevelopment. Nevertheless, they are easy to obtain and are used as outcome measures in several studies.
A study by Bartels evaluating anaesthesia administration and learning disabilities in the Netherlands was published just after the Wilder study in 2009. In this study, parents of 1,143 monozygotic twin pairs reported on anaesthesia use before the age of three and again between the ages of three and 12 years. Near the age of 12, educational achievement and cognitive problems were assessed with standardized tests and teacher ratings. Results showed that twins who were exposed to anaesthesia before the age of three had significantly lower educational achievement scores and significantly more cognitive problems than twins not exposed to anaesthesia. However, there was one exception: the unexposed co-twin did not differ from their exposed co-twin. The study concluded that there is no evidence for a causal relationship between anaesthesia administration and later learning-related outcomes in this sample.7
Another study by Hansen from Denmark published in 2011 compared test scores at 9th grade in 2,689 children that underwent inguinal hernia repair in infancy and a randomly selected age-matched five per cent population sample consisting of 14,575 individuals. The exposure group performed worse than the control group but the difference was not statistically significant. However, there was a higher test score nonattainment rate among the hernia group that could suggest that a subgroup of these children are developmentally disadvantaged compared with the background population. Nonattainment is defined as the child being unable to sit for the test for whatever reason. This includes children that are unable to sit for tests due to significant neurodevelopmental or behavioural problems.8
Another Danish study by Clausen published in 2017, compared academic achievement in 509 children with cleft lip and/or palate that had received anaesthesia and a five per cent sample of the population (14,677 adolescents). Compared to controls there was evidence that children with cleft palate alone had lower test scores while there was no difference compared to controls for either cleft lip alone or cleft lip and palate. In addition, the cleft palate alone group was also more likely to have nonattainment scores.9
A primary cohort study by Glatz from Sweden in 2017 examined 33,514 children with one anaesthesia and surgery exposure before four years of age and no subsequent hospitalization and 159,619 matched unexposed control children. In addition, 3,640 children with multiple surgical procedures before age four were studied. The mean school grades at age 16 years and IQ test scores at military conscription at age 18 years were assessed. The mean difference between the exposed cohort and unexposed cohort was estimated in a model that included sex, month of birth during the same year, gestational age at delivery, Apgar score at five minutes, maternal and paternal educational levels, annual taxable household income, cohabiting parents, and number of siblings. Among 33,514 exposed children and 159,619 unexposed children in the primary study cohort, one exposure before four years of age was associated with a statistically significant mean difference of 0.41% lower school grades and 0.97% lower IQ test scores. The magnitude of the difference was the same after multiple exposures. There was no difference in school grades with one exposure before six months, seven to 12 months, 13 to 24 months, or 25 to 36 months of age. The overall difference was markedly less than the differences associated with sex, maternal educational level, or month of birth during the same year. While this study did find evidence of an association, it should be noted that the difference was less than one per cent in school grades and IQ scores, which is very small.10
There were two studies conducted in Canada that examined the association between anaesthesia in early childhood and the Early Development Index (EDI). The EDI is a validated assessment of a child’s readiness to engage in school activities in five major domains: physical health, social knowledge and competence, emotional health, language and cognitive development and communication skills and general knowledge.
The first Canadian cohort retrospective study by O’Leary in August 2016 included sibling pairs aged five to six years with the same birth mother who had Early Development Instrument (EDI) data completed and had surgery with general anaesthesia from birth to EDI completion. This was a provincial study in Ontario. The main outcome and measure was early developmental vulnerability, defined as any major domain of the EDI in the lowest tenth percentile of the Ontario population. A total of 10,897 sibling pairs were subsequently identified including 2,346 with only one child exposed to surgery. Again, a very small increase in early developmental vulnerability was seen in the exposed group compared with the unexposed group of children (25.6 per cent versus 25 per cent), however, this difference was not significant. There was no difference in odds of early developmental vulnerability with increasing frequency of exposure. The results were adjusted to account for confounding factors: age at EDI completion, sex, mother’s age at birth and eldest sibling status. They concluded that children who had surgical procedures requiring general anaesthesia before primary school entry were not found to be at increased risk of adverse child development outcomes compared with their biological siblings who did not have surgery. These findings further demonstrate that anaesthesia exposure in early childhood is not associated with detectable adverse child development outcomes.11
The other Canadian cohort retrospective study by Graham was conducted in the province of Manitoba and published in October 2016. The EDI for children less than four years of age exposed to GA was compared to those children with no GA exposure. A total of 18,056 children were studied: 3,850 exposed to a single GA and 620 exposed to two or more GA, were matched to 13,586 non-exposed children. In children less than two years of age, there was no independent association between single or multiple GA exposure and EDI results. Paradoxically, single exposure between two and four years of age was associated with deficits, most significant for communication/general knowledge and language/cognition domains. Multiple GA exposure at the age of two to four years did not confer greater risk than single GA exposure. Known sociodemographic and physical confounders were incorporated in the analysis. The study detected a difference that was very small but was statistically significant. The clinical significance of this very small added risk remains uncertain. In addition, these findings refute the assumption that the earlier the GA exposure in children, the greater the likelihood of long-term neurocognitive risk.12
Most of the studies so far are not sufficiently powered to determine if multiple exposures pose any greater risk than single exposure.
Behaviour disorders and learning disabilities instead of school grades have also been used as outcomes in children exposed to anaesthesia early in life. Of the studies published thus far, several but not all have found evidence for an association between surgery and anaesthesia in early life and increased risk of behavioural disorder or learning disability diagnoses. The association is greater with multiple exposures.1 In a study published in 2016, cognitive outcomes following a single and relatively brief anaesthesia exposure were examined in the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) study. This was a sibling-matched cohort of healthy children at four university-based U.S. paediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently eight to 15 years old. The exposed siblings were healthy at the time of surgery/anaesthesia. Neurocognitive and behaviour outcomes were prospectively assessed with retrospectively documented anaesthesia exposure data. A single exposure to general anaesthesia during inguinal hernia surgery in the exposed sibling was compared to no anaesthesia exposure in the unexposed sibling, before age 36 months. The primary outcome was global cognitive function. Secondary outcomes included domain-specific neurocognitive functions and behaviour. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behaviour. Among the 105 sibling pairs, the exposed siblings and the unexposed siblings had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anaesthetic agents, and anaesthesia duration ranged from 20 to 240 minutes. Mean IQ scores between exposed siblings were not statistically significantly different. In addition, no statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behaviour.13
A dose-response relationship has been detected with increasing numbers of co-administered drugs. However, the dose and duration vary widely between procedures making it difficult to measure toxic effects within the study groups. Prospective, age-adjusted documentation of the concentration of the vapour anaesthesia or cumulative milligram per kilogram amounts of intravenous drugs would give better results.5
One of the greatest challenges in examining anaesthesia neurotoxicity is in separating the direct toxic effect of the general anaesthetic on the brain from indirect effects of anaesthesia and surgery disturbing normal physiology. Indirect effects of anaesthesia include hypoxia, hyperoxia, hypotension and hypothermia. Indirect effects of surgery include the stress response, systemic inflammation, pain, and inadequate nutrition. To study the direct effects of surgery or anaesthesia alone is not ethical and almost impossible. These indirect effects may also bias results when comparing general anaesthesia to spinal anaesthesia for surgical procedures.5
The association between general anaesthesia and neurodevelopment is heavily confounded by factors throughout the life course of the child. These include5:
Much larger sample sizes comparing exposed with unexposed children in a 1:4 ratio to maximize statistical power and using other sensitive outcome measures in addition to school grades is ideal. Large sample sizes are also required due to the attrition of subjects during the long follow up period of analysis. The amount of missing data and the reasons for this are frequently omitted. This reduces precision and may bias results if the outcome data are missing non-randomly.5
Randomized controlled trials are the gold standard of scientific analysis. To date there is only one randomized controlled study published in 2019 by McCann (the GAS trial) that has compared neurodevelopmental outcomes with general anesthesia and awake-regional anaesthesia.14 This was a study of infants less than a year old approximately, who underwent inguinal hernia repair and were randomized to have either a sevoflurane (vapour) based general anaesthetic or have awake-regional anaesthesia (using local anaesthetics). The anaesthesiologists were not blinded. However, at five years of age, the individuals administering the neurodevelopmental assessments of full-scale intelligence quotient (FSIQ) were blinded from the type anaesthesia given. Of the 722 infants, 363 received awake-regional anaesthesia and 359 received general anaesthesia. Primary outcome data was received for 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The mean FSIQ score for the awake-regional group was 99.08 and 98.97 for the general anaesthesia group. The mean difference in FSIQ score was negligible providing strong evidence of equivalence. An intention-to-treat analysis provided similar results to those of the per-protocol analysis. The conclusion of the study was that an anaesthetic of less than one hour in early infancy does not alter neurodevelopmental outcome at five years of age compared with awake-regional anaesthesia in a predominantly male study population.
There have been no other randomized trials because these trials are difficult to conduct. Children would need to be assigned to general anaesthesia, regional anaesthesia versus no anaesthesia and no surgery. Clearly, this is extremely difficult both ethically and clinically. Therefore, large prospective cohort studies with rigorous control of confounders have been used to investigate neurodevelopmental outcomes. Twin or sibling studies attempt to eliminate confounding by genetic or environmental factors. In a monozygotic concordant/discordant design, subjects in each group share the same genetic and family level environmental factors. Differences in neurodevelopmental outcome across the groups would then reflect the toxic effect of general anaesthesia and/or surgery. Longitudinal studies with repeated assessments would allow the twin children to serve as their own controls. Obtaining large sample sizes in twin studies to achieve the same statistical power is often difficult. In parallel, animal studies that can be better applied to humans are required. Researchers will need to carefully control for physiological parameters as well as anaesthetic dosing.5
Given all of these challenges, it may never be possible to demonstrate anaesthetic neurotoxicity in conventional clinical trials. However, this remains the hottest area of research in paediatric anaesthesia.
The human studies provide mixed evidence of an association between anaesthesia exposure in early childhood and later deficits in a range of neurodevelopmental outcomes. When added risk has been observed, it is very small. The variations in examined outcomes and generally small differences seen in human studies are not consistent with the preclinical data given the predominantly short exposures and ranges of population and outcomes assessed. However, the strong likelihood of confounding influences in these studies, which are predominantly cohort studies, means that human evidence for any association can only be regarded as very weak evidence that anaesthesia actually causes these poorer outcomes. Thus, any recommendations for changing practice, including the FDA warning, continue to be driven largely by preclinical evidence. In contrast, there is stronger human evidence that a single brief exposure in a healthy infant is not associated with poorer neurodevelopmental outcome.1
There is at present no conclusive evidence or consensus that general anaesthesia harms the developing brain. Childhood general anaesthesia is typically comprised of short procedures and is likely to carry low risk. The evidence base is mainly retrospective observational studies whose subjects were anaesthetized in the 1970s and 1990s. There have been widespread changes in practice including the use of safer drugs and better multi-parameter monitoring that includes pulse oximetry and capnography. In addition, there are differences in fluid management as well as who is delivering anaesthesia to children.5
Withholding general anaesthesia can lead to excessive pain and the associated strong stress response is also thought to impair neurodevelopment. Furthermore, deferring or delaying general anaesthesia can result in prolonged pain as well as other physical or psychosocial harms. Therefore, careful individual consideration is necessary. The general consensus at this point is to avoid unnecessary anaesthesia but there are no recommended changes to clinical practice.
Although the evidence at this point demonstrates the safety of general anaesthesia on the developing brain, it is important to note that there are risks of severe complications of general anaesthetics. These risks are extremely low throughout Canada and in Ontario, these risks are less than one in a million.
Oral Health welcomes this original article.
About the Author
Gino Gizzarelli completed his first degree in 1995 at the University of Toronto in pharmacy. He worked as a full-time clinical pharmacist at Toronto General Hospital for 2 years before returning back to the University of Toronto to study dentistry. Following his dental degree in 2001, he continued his studies in the same university and completed a 3-year Master’s degree in Dental Anaesthesia with training at Sick Kids, Toronto East and Toronto General hospitals. All throughout, Gino has maintained his part-time clinical pharmacist position. Since graduation, he provides general anaesthesia and sedation services in dental offices throughout Ontario. In addition, he has been an expert witness and has lectured at the University of Toronto Faculty of Dentistry as well as various conferences and CE courses