We read with interest the systematic review and meta-analysis by Lateiresh et al. 1, evaluating the efficacy and safety of intranasal dexmedetomidine combined with esketamine compared with dexmedetomidine alone for pediatric premedication. The authors should be commended for addressing a clinically relevant topic and for incorporating trial sequential analysis and GRADE methodology. The reported reduction in emergence delirium and the faster onset of sedation with the combination regimen are appealing findings. However, several methodological considerations warrant a more cautious interpretation. First, the degree of clinical heterogeneity across included trials appears substantial despite statistical pooling. Included studies varied in dosing regimens, surgical populations, and perioperative management. Emergence delirium is highly sensitive to factors such as anesthetic technique, volatile exposure, and pain control 2. In this context, combining heterogeneous trials assumes a level of comparability that may not be fully justified. Notably, prediction intervals for key outcomes are wide and cross the line of no effect, suggesting that the observed benefit may not be consistent across clinical settings. Second, the interpretation of emergence delirium as a homogeneous endpoint deserves further scrutiny. Emergence delirium is a multifactorial phenomenon influenced by preoperative anxiety, anesthetic depth, and postoperative analgesia 2, 3. Variability in these elements across trials may confound the observed association, making it difficult to attribute the effect specifically to the pharmacological combination. A further methodological concern relates to the handling of outcome variability. The use of imputed or assumed standard deviations for mask acceptance introduces uncertainty in the weighting and precision of pooled estimates. While sensitivity analyses were performed, consistency across assumptions does not necessarily imply robustness when primary data are limited. Moreover, the trial sequential analysis provides an important but underemphasized signal. Although conventional meta-analytic thresholds suggest benefit for emergence delirium, the required information size was not reached. This indicates that the available evidence remains inconclusive and potentially subject to random error 4. From a clinical perspective, the magnitude of several statistically significant effects appears modest. A reduction in sedation onset of approximately four minutes and a decrease in PACU stay of less than two minutes may have limited relevance at the individual patient level, even if operationally meaningful in high-volume settings. Distinguishing statistical significance from clinical importance is therefore essential. Finally, all included studies were conducted within a single geographic context, which may limit generalizability. Differences in perioperative practices and patient characteristics may influence both efficacy and safety outcomes. This study provides a valuable synthesis and supports the feasibility of combining dexmedetomidine and esketamine in pediatric premedication. However, the observed benefits should be interpreted within the context of clinical heterogeneity, outcome complexity, and incomplete evidence accrual. Future studies would benefit from standardized perioperative protocols, harmonized definitions of emergence delirium, and pragmatic multicenter designs aimed at isolating pharmacologic effects from contextual influences. Like a sharply focused image built from blurred exposures, the apparent precision of pooled estimates may conceal variability that remains clinically decisive. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Madeo et al. (Tue,) studied this question.