Anesthesia and the developing brain: A way forward for laboratory and clinical research

In 2017 a group of international experts met for the second international conference on paediatric anaesthesia and neurotoxicity titled: International Conference on Pediatric Anesthesia and Neurotoxicity: From the GAS Study to future collaborative trials. This paper summarises the discussions and conclusions reached by that group. After acknowledging that expert opinion divided over the applicability of preclinical trials to humans, the interpretation of human studies and how these findings should be applied to clinical practice. The paper goes on to summarise recent clinical trials and their findings. The conference identified key areas for future research as follows:

• The need for high-quality preclinical studies, both basic and translational, to evaluate mechanisms of toxicity and to inform choice of anaesthetic techniques and/or mitigating strategies.
• Cohort studies with rich sources of data and large enough to detect small outcome differences are required to better characterize neurodevelopmental domains potentially affected in children, identify vulnerable populations, and to establish clinical risk modifiers.
• Carefully designed and adequately powered clinical trials testing plausible interventions in relevant patient populations are required for translation of research to clinical practice.

It was highlighted that future directions for preclinical studies should aim to better understand the biological mechanisms / pathways underlying anaesthesia neurotoxicity, identify safer anaesthetic techniques, elucidate potential mitigating strategies and identify potential risk modifiers. Mitigating strategies discussed include limiting the duration of exposure and dose of anaesthetic agents for example by combining regional and general anaesthesia. The TREX trial is one study that examines a potential mitigating strategy. Although animal studies have looked at potential protective agents and mitigating strategies, the conference concluded that there is currently no data to support alternative anaesthetic strategies.

The group emphasised that future cohort studies need to focus on children with specific comorbities and with prolonged or multiple exposures. Well-designed cohort studies are needed to define: which children are at increased risk, which specific outcome domains are affected, whether an anaesthesia neurotoxicity phenotype can be identified and whether a specific developmental window of vulnerability exists. Determining appropriate outcome measures in clinical trials remains a challenge as there is ongoing debate as to which neurological, neuropshycological and neurobehavioural outcomes should be tested at different ages. Currently available outcomes may have limited sensitivity to detect deficits in specific domains of neurodevelopement.

The group highlighted the importance of future Randomised controlled trials but acknowledged the difficulties they present including which patients, interventions and mitigating strategies to include, appropriate control group selection, recruitment of sufficient numbers, the long lag time between intervention to end point data collection and cost.

Take Home Message
This paper provides an excellent summary of the challenges faced by researchers examining the issue of neurotoxicity and clinicians trying to interpret the data. The group calls for a multidisciplinary collaborative approach to future research and urgers researchers to consider other aspects of perioperative care that may have an impact neurodevelopment.

Reviewed by: Dr Catherine Olweny