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Is this your (paediatric patient's) brain on (anaesthetic) drugs?

The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans

Loepke, Andreas W.; Hansen, Tom G.

European Journal of Anaesthesiology (EJA): May 2015 - Volume 32 - Issue 5 - p 298–300
doi: 10.1097/EJA.0000000000000148
Invited commentary
Free

From the Department of Anesthesiology, University of Cincinnati College of Medicine, Division of Pediatric Cardiac Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA (AWL), and Department of Anesthesiology and Intensive Care, Odense University Hospital, and Clinical Institute, Anesthesiology, University of Southern Denmark, Odense, Denmark (TGH)

Correspondence to Dr Andreas W. Loepke, Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA Tel: +1 513 636 4408; fax: +1 513 636 7337; e-mail: pedsanesthesia@gmail.com

This Invited Commentary accompanies the following original article:

Ko W-R, Huang J-Y, Chiang Y-C, et al. Risk of autistic disorder after exposure to general anaesthesia and surgery. A nationwide, retrospective matched cohort study. Eur J Anaesthesiol 2015; 32:303–310.

A popular advertising campaign in the 1980s and 1990s illustrated the dangers of drug and alcohol abuse for the teenage brain by showing a raw egg (‘This is your brain’) being cracked and fried in a pan (‘This is your brain on drugs’). In a sense, this was a simplified representation of the phenotype of drug use in the developing teenage brain (https://www.youtube.com/watch?v=ub_a2t0ZfTs; Accessed June 2014). Currently, researchers are trying to identify whether there exists a neurological phenotype following early childhood exposure to a class of therapeutic drugs, anaesthetics and sedatives. Concerns for potential harmful effects of anaesthetics on brain development in young children undergoing surgical procedures were first raised by animal studies demonstrating widespread cell death of neurones and oligodendrocytes, reductions in neurotrophic factors, alterations in synaptic and dendritic densities, disintegration of the cytoskeleton and long-term neurocognitive impairment following anaesthetic exposure early in life.1 Subsequently, epidemiological studies established an association between surgical exposure during the first 3 to 4 years of life with learning disabilities, behavioural and developmental disorders or academic underachievement. However, potent confounders, such as the surgical procedure, the underlying illness, postoperative pain and inflammatory response preclude establishing any causative relationship. Fortunately for patients and practitioners, the effect on neurocognitive outcome is not obvious enough to cause overt mental retardation in all children undergoing surgery, and several studies did not even observe any subtle effects until children were exposed more than once. Complicating the search for a potential phenotype is the fact that it is currently unclear whether certain neurological domains or specific cognitive skills, such as reading, writing, arithmetic or executive function, are specifically affected following exposure.

The biological plausibility for potential interference with brain development is rooted in the potent effects of anaesthetic drugs on glutamate's NMDA (N-methyl-D-aspartate) and/or GABA (γ-aminobutyrate) receptors, both of which play critical roles in normal brain development. During brain development, GABA directs cell proliferation, neuroblast migration and dendritic maturation.2 Developmental NMDA receptor stimulation fosters survival and maturation of some neurones.3 Moreover, the relative contributions of these two main excitatory and inhibitory neurotransmitters, respectively, are instrumental in maintaining the adequate balance of excitation and inhibition, which is vital for proper brain function and could be altered by exposure to anaesthetics.4 Many childhood surgical procedures occur under 3 to 4 years of age and are predominantly performed in boys.5

It seems sensible, therefore, to examine whether early interference with NMDA and GABA receptor signalling in childhood may lead to subsequent neurodevelopmental disorders, such as autism spectrum disorder (ASD). Autism spectrum disorder is a heterogeneous disability diagnosed with an increasing frequency (1.5% of U.S. children) that includes abnormalities in communication, behaviour, language or intellectual abilities. Early deficits in communicative and social skills are often observed prior to 18 months of age, and boys are more frequently afflicted than girls by a factor of 4 : 1. Possible aetiological factors include not only genetic components (with a reported heritability of 90%), but also prenatal and environmental factors. Importantly, it has been speculated that this disorder may arise from an abnormal ratio of excitatory to inhibitory neurotransmitters in the brain.6 The current diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) distinguish between three categories: autism disorder; Asperger's syndrome; and not otherwise specified pervasive developmental disorder (‘atypical autism’).7

In this edition of the journal, Ko et al.8 utilised the National Health Insurance Research Database of Taiwan, a large sampling of approximately 4% of the entire population, to study whether exposure to general anaesthesia may be associated with a subsequent diagnosis of ASD. Out of the 114 435 children born between 2001 and 2007, they matched 5197 children (3672 boys and 1525 girls) previously exposed to surgery with anaesthesia prior to 2 years of age, lacking an autism diagnosis prior to exposure, with 20 788 (1 : 4) unexposed control individuals. The authors used International Classification of Diseases-Clinical Modification, 9th Revision (ICD-9-CM) procedural codes to identify anaesthetic exposures and diagnostic code 299.00 for a diagnosis of autistic disorder. They also collected data on potentially confounding diagnoses, such as perinatal complications, congenital anomalies, other neurological disorders or endocrine diseases, as well as geographical location and parental occupation. Unfortunately, no information was available regarding parental age and level of education. Using a multivariate proportional hazard regression, the authors detected an association between both congenital anomalies and neurological disorders with a subsequent diagnosis of autism, as well as an increased likelihood of surgery with anaesthesia. However, before or after adjustment for confounders, an anaesthetic exposure prior to 2 years of age was not associated with a subsequent diagnosis of ASD, according to ICD-9-CM code 299.00, even when multiple exposures and exposures under 4 months of age were considered.

A particular strength of that study is that it represents the first large, representative sampling of almost an entire Asian country's population (99% insured). Previous epidemiological studies were confined to data sets from the United States, Australia or European countries. Interestingly, using learning disabilities, developmental abnormalities, behavioural disorders or academic performance as outcome measures, postexposure abnormalities seemed to be confined to American and Australian children, whereas studies from European countries returned predominantly negative results.9 However, previously exposed Danish children, although not scoring lower than their unexposed peers on a nationwide 9th Grade examination, were slightly less likely to sit the test, with an odds ratio of 1.13 (95% CI 0.98 to 1.31) for children undergoing inguinal hernia repair in infancy,10 and 1.37 (95% CI 1.11 to 1.68) for children undergoing repair of pyloric stenosis before the age of 3 months.11

Importantly, ASD is a disability of unknown cause that comprises a heterogeneous group of symptoms, and is therefore not easily classified by one single diagnostic code. Asperger's, Rett and Fragile X syndromes, as well as pervasive developmental disorder – not otherwise specified, also referred to as ‘atypical autism’ – represent closely associated disorders with distinct ICD-9 codes and were therefore not captured in the present study. ASD has a significant genetic component and chromosomal data were obviously not included in an insurance database.

It is still not clear whether there exists a specific neurological phenotype associated with exposure to surgery with general anaesthesia early in life. It would obviously represent a major threat to child health if animal studies demonstrating widespread neuronal elimination, brain structural abnormalities and neurocognitive deficits following anaesthetic exposure early in life applied directly to humans. The present study seems to suggest that classical autism may not be part of any potential neurological phenotype, at least not in Taiwanese children. However, given the immense importance for individual wellbeing as well as societal health, intensified research efforts are needed to determine whether or not surgical procedures with general anaesthesia have any long-term effects on the developing human brain. Furthermore, if this were the case, it is imperative to identify the population most at risk and the underlying mechanism to devise targeted mitigating strategies. Paediatric anaesthesiologists do not want to have to look back saying ‘This was the deleterious phenotype for our paediatric patient's brain on anaesthetic drugs’.

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Acknowledgements relating to this article

Assistance with the commentary: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Comment from the editor: this invited commentary was checked and accepted by the editors, but was not sent for external peer review.

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References

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