Background

Worldwide, millions of children are exposed to general anesthesia every year.1 General anesthesia consists of a wide variety of agents including intravenous anesthetics, such as propofol, ketamine, benzodiazepines, etomidate and barbiturates, and inhalational agents that include halothane, sevoflurane, isoflurane, nitrous oxide, xenon and desflurane. These compounds are chemically very diverse, but interestingly have very similar proposed mechanisms of action.2 Although these surgical procedures are life-saving, questions still remain regarding the long-term effects and safety of exposure to these anesthetics. Multiple research studies have been performed investigating the administration of general anesthesia on the developing brain and its impact on the development of specific learning disorder (SpLD).

Neurological maturation is complicated, and research studies have used learning disabilities as an outcome to measure the impact of general anesthesia on the developing brain. Learning disabilities have many components, traditionally including reading, mathematics and writing.3 Recently, the most updated version of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, has broadened the diagnosis of learning disabilities to include an overarching umbrella diagnosis of SpLD that includes deficits related to academic performance.3 The criteria of SpLD now describes "shortcomings in general academic skills and provide detailed specifiers for the areas of reading, mathematics and written expression".3^(p.1) The generalization of the SpLD diagnosis helps to address the core issue of the neurological deficit and moves away from categorizing one symptom as the actual diagnosis.3 This provides a holistic approach to treating these patients without limitations to the presenting symptoms because oftentimes one symptom can be a reflection of a larger issue.

Research has been conducted in rodents and non-human primates, which has linked the administration of general anesthesia during periods of rapid brain growth or synaptogenesis with an increase in neuronal death, leading to long-term neurocognitive deficits.4 This has raised significant concerns for the implications in humans, specifically for children under the age of two years as the critical period of accelerated synaptogenesis is known to occur from the third trimester up until the age of 22 years. Normal brain development is dependent on gamma-aminobutyric acid receptors (GABAA) and N-methyl-D-aspartate receptors (NMDA) mediated neuronal activity.2 The proposed mechanism of action of the anesthetic drugs is primarily by two mechanisms that include an increase in the inhibitory effect of GABAA and a decrease in the excitatory effects of NMDA. Pediatric anesthesia utilizes drugs that act on both mechanisms to induce and maintain a level of anesthesia that is conducive to the performance of surgical procedures.5 The exposure to general anesthesia poses a concern because it could interfere with normal synaptogenesis, which could ultimately result in SpLD.

The research that has been conducted regarding this topic has demonstrated the negative effects of repeated exposure to anesthesia during the period of rapid brain growth. Multiple exposure to anesthetics in neonatal and young pediatric patients has shown to be a significant independent risk factor for the development of SpLD.1 For example, in a population-based birth cohort study by Wilder et al.,6 children who had multiple exposure to general anesthesia were at an increased risk for developing learning disabilities as demonstrated by deficits in reading, written language and mathematics, and measured by Intelligence Quotient and standardized achievement testing. However, this is not the case with a single exposure to anesthesia. An important consideration is that the need for anesthesia can be a marker for factors that contribute to the development of SpLD.1 For instance, infants requiring surgery may be premature, have adverse peripartum events or congenital diseases. Although it is difficult to quantify the cause of SpLD due to multiple variables, it is important to establish whether multiple exposure to anesthesia before the age of two years is a contributing factor to the development of SpLD.

The magnitude of the impact of a learning disability on a child could be life-altering. A learning disability could affect quality of life.7 The diagnosis of SpLD can cause emotional distress, and the inability of children to relate to their peers and hence be stigmatized. Many cultures, especially those in developed countries, place a high value on academic achievement, and this often equates with self-worth. Specific learning disorder can make a child question their value, leading to anxiety, depression and isolation.7 The negative impact of SpLD does not stop with the child, but parents also suffer detrimental consequences. Parents experience poor quality of life in relation to social relationships and the environment.8 Social aspects include poor personal and sexual relationships, a decrease in social support and an unsatisfactory social and home life.8 The environmental effects include decreases in safety and security, recreation, transportation, resources and health services.8 Specific learning disorder has a grave effect beyond the child, which influences the family as a whole. Because of the negative, far-reaching effects that SpLD can have, the topic of anesthesia causing SpLD needs further investigation to make pediatric anesthesia as safe as possible.

It is important to raise questions to ensure pediatric anesthesia is at the pinnacle of safety to enable healthcare providers to make informed decisions regarding surgical procedures in neonates and young children. If in fact, multiple exposure does cause SpLD, healthcare providers could utilize this evidence to deliver best practice and limit exposure of pediatric patients to anesthesia by altering anesthetic regimens, determining medical necessity of surgery, making the decision to delay surgery and careful consideration of the general timing of surgery in these patients. A search of the JBI Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews, MEDLINE and CINAHL found no existing systematic review with this particular research question. Although there are systematic reviews related to this topic, none had specific parameters evaluating SpLD and the exposure to general anesthesia under the age of two years.4

Inclusion criteria

Types of participants

The current review will consider studies that include pediatric patients aged two years and under. Pediatric patients with a history of neurologic or psychological illness, head trauma or mental retardation at the time of the study will be excluded.

Types of exposure

The current review will consider studies that investigate multiple exposure (>1) to general anesthesia versus no exposure to general anesthesia.

Outcomes

The outcomes considered will be the actual diagnosis of SpLD or any of the components of the criteria for the diagnosis of SpLD that generally consists of the presence of low academic achievement. Although there is not a single test or marker for SpLD, the overall diagnosis includes deficiencies in reading, mathematics or writing skills.3 Due to the broad criteria for the diagnosis of SpLD, studies that investigate any sort of academic shortcoming will be considered in this review.

Types of studies

The current review will include prospective and retrospective cohort studies and case-controlled studies for inclusion.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article. A second search, using all identified keywords and index terms, will then be undertaken across all included databases. Third, the reference list of all identified reports and articles will be searched for additional studies. Studies published in the English language will be considered for inclusion in this review. Animal studies, evaluating the effects of general anesthesia on the brain, began in the last four decades. Our preliminary search of the literature yielded only articles published after 1975. Hence, only articles published after 1975 will be included.

The databases to be searched include:

MEDLINE

EMBASE

Web of Science.

The search for unpublished studies will include:

ProQuest database for theses and dissertations.

Initial keywords to be used will be: Anesthesia adverse effects AND neurodevelopmental AND ^*developmental AND pediatric AND anesthesia AND general anesthesia AND learning disabilities AND specific learning disorder AND brain AND growth development AND pediatric^*.

Assessment of methodological quality

Papers selected for retrieval will be assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (Appendix I). Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer.

Data extraction

Quantitative data will be extracted from papers included in the review by two independent reviewers using the standardized data extraction tool from JBI-MAStARI (Appendix II). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using Comprehensive Meta-Analysis software (BioStat Englewood, NJ, USA). All results will be subject to double data entry. Effect sizes, expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals, will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-square and also explored using subgroup analyses based on the different study designs included in this review. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Appendix I: Appraisal instruments

MAStARI appraisal instrument

Appendix II: Data extraction instruments

MAStARI data extraction instrument

References