Key issues that need to be addressed by clinical studies include what should be considered as adverse neurodevelopmental outcome and the age at risk. Neurodevelopmental outcome could be assessed as the presence of neurodevelopmental disorders, such as autism, mental retardation, language delay, learning disability, or attention deficit hyperactivity disorder.61–63
To date, studies examining the association of anaesthesia exposure with neurodevelopmental outcome have adopted this approach.55–59
However, objective evaluation of neurodevelopmental abnormality requires direct assessment of neurocognitive functions using standardized neuropsychological instruments. Neuropsychological assessment in a developing child is very different than in adults. First, neuropsychological assessment instruments in children are age-specific and those available for the very young do not always predict later functions.64
Secondly, many of the neurocognitive functions are not yet fully developed at the time of exposure.65,66
Therefore, pre-exposure ‘baseline’ neuropsychological assessment of young children would not even be possible as in adults.
The age of vulnerability in children cannot be extrapolated easily from the clinical studies because cross-species translation of brain development is still an area of ongoing study. The vulnerable period of injury has been consistently demonstrated to be during peak synaptogenesis.7,10,30,50
Therefore, our current understanding of human brain development may be informative in choosing the age most likely to be at risk for anaesthetic neurotoxicity. In the human brain, there are significant regional differences in the timing for peak synaptogenesis. The earliest is in the primary sensorimotor cortex, occurring around birth. This is followed by the parietal and temporal association cortex, important in language and spatial attention, where peak synaptogenesis occurs at around 9 months. The last region to peak in synaptogenesis is in the prefrontal cortex, which occurs at age 2–3 yr. The prefrontal cortex is key in executive function and integrative and modulatory brain function. Since peak synaptogenesis occurs between birth and 2–3 yr of age,65,67,68
the vulnerability period for anaesthetic-induced neurotoxicity might be up to 36 months of age in the developing human brain.
Currently, there are two large-scale studies underway that attempt to address the issue of anaesthetic neurotoxicity in children. The GAS study is an international randomized trial comparing general sevoflurane anaesthesia with regional anaesthesia in 600 infants undergoing inguinal hernia repair. The follow-up period will be 5 yr, with evaluation performed at ages 2 and 5 yr. The evaluation at age 2 will be performed using the Bayley Scales for Infant Development-III, and the evaluation at age 5 will include the Wechsler Preschool and Primary Scale of Intelligence-III and additional neuropsychological tests within NEPSY II (second edition of the neuropsychological test battery for children and adolescents).
The PANDA (Pediatric Anesthesia and NeuroDevelopment Assessment) study is a multisite study that will involve eight US study sites. It is an ambi-directional, sibling-matched cohort study that will enrol a total of 1000 children or 500 sibling pairs. The anaesthesia exposure will be limited to a single episode of general anaesthesia for inguinal hernia repair in ASA I and II patients before 36 months of age. The study will perform an extensive neuropsychological battery in children between age 8 and 15 yr (Table ).
Proposed neurocognitive outcomes and assessment instruments in the PANDA study
Results from the PANDA study will be applicable to children undergoing elective procedures who are otherwise healthy, which constitute the great majority of patients in the USA. If anaesthetic exposure is found to be without effects in the study patients, reassurance could be offered to millions of parents. However, other patients who have significant co-morbidities or with more prolonged or frequent exposure to anaesthesia would still need to be examined. Should the study find anaesthesia exposure to have deleterious neurocognitive effects, we must urgently consider alternative strategies in the timing and delivery of anaesthesia care to young children and the development of novel anaesthetic agents with different mechanisms of action with minimal neurotoxic effects. Additional studies would be needed to more specifically determine the age of vulnerability and examine the specific exposure variables related to types of anaesthetic agents, drug doses, and exposure duration. Although additional studies would still be needed depending on the findings from these studies, these large-scale studies should produce data that will contribute significantly in addressing whether the preclinical studies on anaesthetic neurotoxicity are clinically relevant and thus inform clinical decision-making.