Pain control or brain protection: which mechanism defines esketamine?

Lin et al. reported on the use of intravenous esketamine for preventing emergence delirium and negative behavioural changes after paediatric adenotonsillectomy [1]. We commend the authors for their rigorous exploration of pharmacological strategies to mitigate the impact of surgical stress on neurodevelopment and behaviour in children. While these findings offer a valuable intervention for a common clinical challenge, an additional perspective on pharmacological translation and clinical applicability may further the discussion. A fundamental question regarding the protective effects of esketamine needs to be clarified. The results show that children receiving esketamine experienced significantly lower cumulative pain exposure, evidenced by a reduced area under the curve for postoperative pain scores. Improved analgesia addresses a recognised trigger for emergence delirium, as noted by the authors. It is worth considering whether the reduction in delayed behavioural disturbances is primarily a secondary benefit of superior pain control or if it is driven by an independent neuroprotective mechanism. Recent translational literature suggests that subanaesthetic esketamine mitigates neuroinflammation, challenging historical paradigms regarding neurotoxicity in the developing brain [2, 3]. Since robust longitudinal data for pain trajectories and behavioural outcomes are available in this cohort, conducting a formal mediation analysis could quantify the proportion of the treatment effect mediated by analgesia vs. direct neuromodulation. Such an analysis would clarify whether esketamine might offer similar neuroprotection in procedures associated with lower baseline pain burdens. Integrating this prophylactic strategy into existing postoperative protocols also requires careful alignment with current rescue algorithms. Propofol or morphine were utilised in the study protocol as rescue medications for breakthrough emergence delirium and pain. Understanding the precise reduction in the consumption of these specific rescue drugs is critical for hospitals evaluating the incorporation of esketamine into enhanced recovery pathways, particularly because both medications carry risks of respiratory depression after paediatric airway surgery. To facilitate institutional implementation, the existing dataset could be leveraged to report the number needed to treat to prevent one rescue intervention in the recovery room. Showing how prophylactic esketamine might replace traditional rescue algorithms aligns with the growing momentum toward opioid-sparing anaesthesia [4]. This would provide a safety-driven rationale for translating this research into standard clinical policy. The findings suggest that intra-operative modulation of the glutamatergic system may serve as a preventive neuropsychiatric intervention rather than merely an analgesic adjunct. Notably, exploring targeted multimodal neuroprotection could be highly relevant for high stress procedures. For instance, the synergistic use of esketamine and dexmedetomidine could be investigated to simultaneously attenuate glutamatergic excitotoxicity and blunt sympathetic surges [5]. Future translational research could build on this foundation by integrating biological markers like inflammatory cytokines or neurophysiological monitoring to map functional connectivity. This would help illuminate how transient pharmacological interventions produce prolonged behavioural benefits.