New study does not support use of dexmedetomidine-remifentanil to change neurodevelopmental outcomes of sevoflurane
Introduction
For the past two decades, the potential neurologic impact of exposure to general anesthesia on the developing brain has been a key question in anesthesia research. A large body of preclinical data suggests the potential neurotoxic impact of numerous anesthetic agents on developing brains. Animal studies have described extensive evidence of neuroapoptosis, maladaptive apoptotic patterns, developmental delays, and total paralysis when exposed to general anesthetics such as benzodiazepines, propofol, thiopental, ketamine, sevoflurane, isoflurane, and nitrous oxide (1,2).
Numerous current targets for anesthetic agents commonly employed in pediatric anesthetic care have been implicated in animal studies of neurotoxicity. Current understanding of the mechanism of anesthetic-induced developmental neurotoxicity (AIDN) is exposure to a general anesthetic before brain synaptogenesis has occurred, causing detrimental neurologic effects. Potentiation of gamma-aminobutyric acid (GABA)A receptors and antagonism of N-methyl-D-aspartic acid (NMDA) receptors are believed to be associated with the pathophysiology of neuroapoptosis (3).
The clinical impact of this concerning animal data is a vital concern but a challenging question to study. The complexity of both development and conditions leading to early exposure to anesthesia can result in a host of confounding issues. These issues limit effective study design and interpretation. Markers of executive function that could be impacted by early neurotoxic events are dynamic and often fully develop later in life (3). Development may conclude many years after data collection and publication (3). Indications for surgery, timing during development of anesthesia exposure, duration of exposure to anesthesia, socioeconomic status, and genetic influences have also been mentioned in the literature as potential confounders (4). Accessibility to healthcare resources, medical comorbidities, preexisting neurocognitive diagnoses, and parental educational status are additional variables that can have a profound impact on development and the ability to interrogate neurodevelopmental outcomes of early childhood exposure to anesthesia (5,6).
Despite these challenges, a small but growing body of thoughtful and reassuring human trials have been performed. The Pediatric Anesthesia Neuro Developmental Assessment (PANDA) project is a sibling-matched cohort study including 105 sibling pairs within 36 months in age from age 8 to 15 years at the time of analysis. A single exposure to general anesthesia before age 36 months occurred for inguinal hernia surgery for one of each of the siblings in sibling pairs, with no anesthesia exposure in the paired sibling. Researchers found that there was no statistically significant difference in intelligence quotient (IQ) scores when measured later in childhood (4). The general anesthesia or awake regional anesthesia in infancy (GAS) trial is a randomized controlled trial that studied the difference in neurodevelopmental outcome between 447 infants older than 26 weeks and younger than 60 weeks gestational age undergoing inguinal herniorrhaphies either under regional anesthesia or sevoflurane general anesthesia. Results demonstrated no significant difference between regional and general anesthesia groups in full scale intelligence quotient (FSIQ) (5). Conversely, Reighard et al. conducted a systematic review and meta-analysis stating that any exposure to general anesthesia was associated with worse behavioral problem scores, cognition, executive function, general development, motor function, and nonverbal reasoning (7).
The recent work of Ji et al. (6) is a welcome addition to this body of thoughtful human trials. The trial is designed to address two key questions. Specifically, is the possible neurotoxic impact of sevoflurane dose-dependent and can standard dexmedetomidine use limit the toxic effects of exposure? The trial compares the use of dexmedetomidine and remifentanil in conjunction with sevoflurane in an experimental group with sevoflurane alone in a control group in the pediatric population. Bispectral index (BIS) monitoring was employed to standardize and limit total sevoflurane exposure.
This approach is clever and important in developing current knowledge. Comparing long-term neurologic outcomes of the use of specific goal-directed approaches to anesthesia care in the pediatric population is important and could potentially guide future clinical choices.
Study objectives and design
Ji et al. aim to examine the comparative impact of different anesthetic techniques on neurodevelopmental outcomes. Specifically, the trial compared an experimental group of children who received dexmedetomidine and remifentanil as adjuncts to sevoflurane, and a control group that received sevoflurane alone in a prospective, double-blind, randomized clinical trial. The trial was designed to examine a hypothesized protective impact of the experimental approach during a single anesthetic exposure.
A total of 400 children under the age of 2 years presenting for non-staged, nonrepetitive surgeries were randomized to receive general anesthesia with either experimental or control protocol. BIS monitoring to target 40 to 60 was employed in both groups to ensure targeted adjustment of sevoflurane. Other aspects of care were standardized in both groups, including monitoring, fluid administration, and analgesia.
When participants reached approximately 30 months of age, they presented to the hospital to complete two validated tools to assess neurodevelopment. The Korean version of the Leiter International Performance Scale was administered by psychologists as a means to examine various cognitive abilities. The Child Behavior Checklist was completed by a primary caregiver to examine multiple areas of emotional and behavioral function. Sample size for this trial was based on the results of the GAS trial and intended to identify a significant hypothesized neuroprotective effect of the experimental approach.
Outcomes, explanation, counterarguments and solutions
Ultimately, 176 children from the experimental group and 169 from the control group were included in the final analysis. The analyzed groups had similar demographics, markers of socioeconomic status, duration of anesthesia, duration of surgery, and BIS values. Amongst these children, there were no significant differences in studied intelligence or behavioral outcomes. These outcomes were observed despite a statistically significant reduction in mean end-tidal sevoflurane that was observed in the experimental group.
Despite the inability to confirm a thought-provoking hypothesis, the results of this trial are potentially impactful. The lack of an obvious negative developmental impact of a single brief anesthetic exposure is clearly supportive of and consistent with the outcomes of both the GAS and PANDA trials. All of these studies suggest the lack of an obvious neurodevelopmental impact of a single brief early childhood exposure to general anesthesia (4,5).
Importantly, the results do not clearly support a role for the widespread use of dexmedetomidine as a neuroprotective addition to standard anesthesia care for young children. These results are similar to the trial of remifentanil dexmedetomidine (TREX) that studied the difference between low-dose sevoflurane with dexmedetomidine and remifentanil as adjuncts in an experimental group with standard-dose sevoflurane alone in a control group and compared the differences in short-term perioperative outcomes following two hours of exposure (8).
Dexmedetomidine is an agent that acts on alpha-2 and imidazoline type 2 receptors. It has numerous suggested neuroprotective effects (9). Accordingly, it may be an appealing target as an adjuvant in the context of concerns related to anesthetic neurotoxicity. While intriguing, widespread use of this agent would not be simple or benign. A large retrospective study demonstrated that pediatric dexmedetomidine use resulted in higher costs, increased duration of post-anesthesia care unit stays, unwanted hemodynamic effects, and did not reduce the incidence of emergence delirium (10). Essentially, widespread use of the agent may have adverse effects. The results reported by Ji et al. do not provide clear evidence to support universal or widespread use of dexmedetomidine to reduce the possible anesthetic-related neurotoxicity. This could allow for a more thoughtful approach to the use of the agent and maybe a springboard for further studies.
The results reported by Ji et al. also do not clearly support a dose-response relationship between sevoflurane and observed untold developmental outcomes. By extension, the results do not directly support the use of targeted BIS monitoring as a means to provide neuroprotection by serving as a means to limit exposure to sevoflurane. This is an insight with potential clinical and pre-clinical implications. However, there are study limitations that could impact the widespread clinical application of these results. Specifically, while a statistically significant reduction in mean end-tidal sevoflurane values was observed in the experimental group, values in both the DEX-R group and control group were within typical clinical ranges for pediatric anesthesia care. This may suggest that the average BIS goal was too permissive or adjustments in sevoflurane were too conservative. In both groups, typical BIS values were close to 40. This value is at the lower range of the suggested window of 40 to 60. A more liberal target range of 50 to 60 may have resulted in what could be viewed as a clinically signification reduction in mean end-tidal values. Interrogation of the hypothesis under these conditions could potentially be more impactful. Accordingly, a more liberal target range should be a consideration in future study designs.
The timing and frequency of neurodevelopmental testing might also impact the applicability of results. Both the GAS and PANDA trials performed testing at later stages of development, with testing occurring at ages 5 years (5) and 10 years (4). Neurodevelopment is dynamic and complex. Data gathered at a later endpoint may allow for easier detection of desired outcomes. Similarly, capturing data at multiple temporal endpoints may have produced a more impactful effort. The addition of other secondary markers of neurodevelopment, including measuring incidence of newly diagnosed learning disabilities, behavioral delays, language delays, and social delays, could also be impactful. These changes could be part of future study design. However, despite these concerns, the current study by Ji et al. is thoughtfully designed and employs validated means to address the key questions.
Sample size and power are clearly concerns in the context of a trial to measure an unknown clinical entity. The use of the GAS trial data as a means to determine sample size was a clever approach to this challenging aspect of study design. It should be noted that the growing body of evidence supporting the relative safety of a single brief exposure to general anesthesia (4-6) may suggest a very large number needed to treat to allow for the hypothesized neurodevelopmental benefits of the reduction in sevoflurane use and the standardized application of dexmedetomidine. This may be a challenging barrier to overcome, possibly requiring multi-center efforts or pivoting to longer duration of anesthetic exposure. Despite possible concerns about power, the results reported by Ji et al. are impactful suggesting no obvious need to alter care and support the body of evidence for the safety of a single exposure to general anesthesia.
It should be noted that Ji et al. conducted this study at a single center in the Republic of Korea. This may lead to unseen confounding concerns, including what the authors describe as the limited ability to generalize data collected from a “homogenous Korean cohort”. While concerning, this approach has the benefit of minimizing certain genetic and cultural confounding variables. Results gathered under these conditions could be viewed as relatively standardized and potentially applicable in other cultural milieus.
Confounding issues are a major concern in the study of the potential neurotoxic impact of exposure to anesthesia (4-6). Results of studies maybe impacted by numerous factors including genetics, socioeconomic factors, access to healthcare, and differing responses to surgical or physiologic stress may alter developmental outcomes. Accordingly, the topic is challenging especially in the context of a single exposure at a single site. Examination of the impact of multiple exposures may be a future direction for study.
Conclusions
Ji et al. present a study that represents one of very few randomized controlled trials analyzing the impact of neurodevelopmental outcomes of general anesthesia exposure in the pediatric population. The work exemplifies a thoughtful approach to the profound challenge of discerning the clinical impact of neurotoxic changes observed in animals following early exposure to general anesthesia.
The authors presented the results of a large, randomized trial designed to determine the potential neuroprotective impact of the use of the combination of dexmedetomidine-remifentanil to reduce exposure to sevoflurane. The results did not support the widespread use of this technique or clear changes to current practices. Additionally, results support existing studies (4,5) that suggest the relative safety of a single brief exposure to general anesthesia.
The key question posed by Ji et al. related to a dose-dependent neurologic response to sevoflurane is profound and significant. A clear relationship may imply causality, support evidence-based changes to anesthetic techniques and support universal electroencephalogram (EEG) monitoring. The effort by Ji et al. is both reassuring and may serve as a framework for future studies including efforts to examine a dose-response relationship.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.
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References
- Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82. [Crossref] [PubMed]
- Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology 2010;112:834-41. [Crossref] [PubMed]
- Chaudhary F, Agrawal DK. Anesthesia-induced Developmental Neurotoxicity in Pediatric Population. J Surg Res (Houst) 2024;7:490-500. [Crossref] [PubMed]
- Sun LS, Li G, Miller TL, et al. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA 2016;315:2312-20. [Crossref] [PubMed]
- McCann ME, de Graaff JC, Dorris L, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet 2019;393:664-77. [Crossref] [PubMed]
- Ji SH, Kang P, Cho SA, et al. Effects of Dexmedetomidine-Remifentanil on Neurodevelopment of Children after Inhalation Anesthesia: A Randomized Clinical Trial. Anesthesiology 2025;143:827-34. [Crossref] [PubMed]
- Reighard C, Junaid S, Jackson WM, et al. Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes: A Systematic Review and Meta-analysis. JAMA Netw Open 2022;5:e2217427. [Crossref] [PubMed]
- Saynhalath R, Disma N, Taverner FJ, et al. Short-term Outcomes in Infants after General Anesthesia with Low-dose Sevoflurane/Dexmedetomidine/Remifentanil versus Standard-dose Sevoflurane (the TREX Trial). Anesthesiology 2024;141:1075-85. [Crossref] [PubMed]
- Tsivitis A, Wang A, Murphy J, et al. Anesthesia, the developing brain, and dexmedetomidine for neuroprotection. Front Neurol 2023;14:1150135. [Crossref] [PubMed]
- Azimaraghi O, Rudolph MI, Luedeke CM, et al. Association of dexmedetomidine use with haemodynamics, postoperative recovery, and cost in paediatric anaesthesia: a hospital registry study. Br J Anaesth 2024;133:326-33. [Crossref] [PubMed]
