Effects of Dexmedetomidine-Remifentanil on Neurodevelopment of Children after Inhalation Anesthesia
A Randomized Clinical Trial
Anesthesiology
Submitted January 2026 by Dr Andrew Hughes
Read by 13 Journal Watch subscribers
Overview/Summary:
This prospective, double-blind RCT compares the neurodevelopmental effect of a single GA exposure using different doses of sevoflurane in children under 2 years of age. Children were randomised to two different GA techniques: sevoflurane alone or lower-dose sevoflurane in combination with dexmedetomidine and remifentanil infusions. The results of the neurodevelopment assessment at 30 months of age are reported in this paper. The primary outcome of Full-Scale IQ assessment at 5 years of age will be reported at a later date.
Methods:
The participants were ASA 1 or 2 children between 1 month and 2 yrs of age undergoing GA for elective, nonstaged and nonrepetitive procedures (urologic, orthopaedic, general, plastic, otolaryngologic, and thoracoscopic surgeries). Exclusion criteria included a history of previous GA, known genetic or chromosomal abnormalities, developmental delay, and a range major medical conditions. Participants were withdrawn from the study if an additional GA was required during the follow up period.
Following IV induction with thiopentone and rocuronium, both groups received maintenance anaesthesia with sevoflurane. From induction through to the end of surgery, the DEX-R group received dexmedetomidine (1 mcg/kg loading dose, followed by 1 mcg/kg/hr) and remifentanil (0.1-0.2 mcg/kg/min), whereas the control group received normal saline at equivalent volumes. In both groups, sevoflurane concentration was adjusted to maintain BIS values 40-60. Participants were assessed at approximately 30 months of age using the Korean version of the Leiter International Performance Scale (standardised nonverbal intelligence assessment tool, administered by a clinical psychologist) and the Child Behaviour Checklist (completed by a primary caregiver)
Results:
- A total of 400 participants were randomised; 345 participants were included in the final analysis (12 had unexpected additional surgeries, 42 lost to follow-up, 1 did not complete full developmental testing for unexplained reasons)
- No significant differences between groups in terms of baseline participant characteristics (mean age approximately 11 months); parental age, educational level and socioeconomic status; distribution of surgical types; duration of anaesthesia (approximately 75 minutes) or surgery; or mean BIS values
- The control group received significantly higher mean end-tidal sevoflurane concentration (2.6% +/- 0.6% vs 1.8% +/- 0.5%, p < 0.001)
- No significant difference between the groups in any of the measured neurodevelopment outcomes
- DEX-R group demonstrated lower HR and systolic BP. Only one patient in each group received vasoactive medication
Context of this study:
The important issue of whether GA causes relevant neurotoxicity in children can only be properly addressed with RCTs, as these minimise the effect of confounding factors. However, as GA is usually required for surgery in children, there are limited clinical scenarios in which children can be randomised to GA vs no GA. To date, the GAS trial is the only RCT comparing GA vs no GA exposure. The GAS trial randomised infants having inguinal hernia repair to GA (median GA duration of 54 minutes) or awake regional anaesthesia and found no difference in neurodevelopment outcome at 5 years of age.
The CF-GAIN study evaluated children with cystic fibrosis randomised to care with differing exposure to GA in early childhood. The study enrolled children who previously participated in an RCT comparing bronchoalveolar-lavage (BAL)-directed therapy (requiring repeated GAs) to standard therapy (not requiring repeat GAs) up until 5 years of age. There were no differences in neurodevelopmental outcome between the groups at approximately 13 years old despite the BAL-directed group undergoing more GA exposures in early childhood.
The RCT discussed in this review adds to the literature by evaluating the neurodevelopmental effect of a single exposure to standard- vs lower-dose sevoflurane GA. The TREX trial, the primary results of which will be reported in the next few years, has a similar trial design, albeit with longer GA duration.
Strengths:
- This trial addresses a topic of great public interest
- It is only the second RCT designed to specifically address the neurotoxicity of sevoflurane GA in young children.
Limitations:
- There was limited separation of treatment (i.e. difference in sevoflurane concentration) between the low dose sevoflurane group and control group (mean end tidal sevoflurane concentration of 1.8% vs 2.6%). This separation is significantly less than what was achieved in the TREX trial (end tidal sevoflurane concentration 0.8% vs 2.5%). This limited dose difference may be insufficient to see an effect
- 30 months old is relatively young for assessing neurodevelopment. Assessment at 5 years old (primary outcome) may be more sensitive for detecting neurodevelopmental differences, with the potential downside of losing more patients to follow up at this later stage
- This study does not address the potential neurotoxicity of longer sevoflurane GAs (i.e. > 2 hours), or propofol-based GAs
Take home message:
The preliminary results of this trial found no neurodevelopmental differences at 30 months of age between young children exposed to a single lower-dose sevoflurane GA (supplemented with dexmedetomidine and remifentanil) compared with a single standard- dose sevoflurane GA. These results show no evidence that lower-dose sevoflurane GA is less neurotoxic, or that dexmedetomidine or remifentanil are neuroprotective in this setting.
The primary outcome results of this trial (to be assessed at 5 years of age) and the similar TREX RCT are awaited.
