ED90 of Remimazolam for Moderate Sedation in Children Undergoing Neurosurgery

Background: Preoperative sedation is critical to alleviate anxiety in children undergoing neurosurgery, but the role of remimazolam is still uncertain such as its unestablished dosing and safety. This study was aimed to determine the 90% effective dose (ED90) of remimazolam for moderate sedation in this pediatric population. Methods: This dose-finding study enrolled children aged 3 months to 6 years scheduled for neurosurgery. The up-and-down method (k-in-a-row, k= 6) was employed to investigate the ED90 of remimazolam for moderate sedation. According to the k-in-a-row rule, one patient received a predefined dose of remimazolam and the dosing assignment of the next patient depended on whether the former patient reached moderate sedation or not. Moderate sedation was assessed using the modified Observer’s Assessment of Alertness/Sedation (MOAA/S). Remimazolam doses ranged from 0.05mg/kg to 0.35mg/kg with a step gradient of 0.05mg/kg. The ED90 and 95% confidence interval (CI) were calculated by centered isotonic regression. Secondary outcomes included drug-related adverse events, the incidence of emergence delirium (ED), and changes in brain network connectivity which were monitored by functional near-infrared spectroscopy (fNIRS). Results: Forty-eight children were enrolled with a median age of 20.5 (9.0, 35.0) months. The ED90 of remimazolam for moderate sedation was 0.28 (95% CI 0.24– 0.42) mg/kg. The incidence of drug-related adverse events was about 12.5%, including respiratory depression and hiccup. The incidence of ED was 62.2%. fNIRS showed increased connectivity in right frontal lobe-right occipital lobe, right frontal lobe-left occipital lobe, and right frontal lobe-left parietal lobe (all P values < 0.05 after correction by false discovery rate). Conclusion: This study reported the ED90 of remimazolam for moderate sedation in neurosurgical children. These results provided important information for the use of remimazolam in children with neurologic disease. Keywords: remimazolam, pediatrics, neurosurgery, moderate sedation, brain network connectivity