Chloral Hydrate’s Impact on Brain Development: From Clinical Safety to Molecular Mechanisms

Pengyi Deng,1,* Chenghao Zhu,1,* Jie Zhang,1 Liling Zhu,1 Ting Xiao,2 Shuangquan Qu1,2 1The School of Pediatrics, Hengyang Medical School, University of South China (Hunan Children’s Hospital), Changsha, Hunan, 410007, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Children’s Hospital of Xiangya School of Medicine, Central South University (Hunan Children’s Hospital), Changsha, Hunan, 410007, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ting Xiao, Email [email protected] Shuangquan Qu, Email [email protected]: Chloral hydrate remains an irreplaceable first-line sedative in pediatric clinical practice, widely used for outpatient procedures and imaging examinations due to its proven efficacy and unique suitability for children. Despite its clinical indispensability, the impact of chloral hydrate on the developing central nervous system (CNS) in children remains largely unelucidated - a critical knowledge gap, given that children’s immature blood-brain barrier (BBB) and high neuronal plasticity render their developing brains more vulnerable to pharmacological agents. Existing evidence demonstrates a significant negative correlation between the duration of chloral hydrate use and pediatric intelligence quotient (PIQ): longer usage is associated with lower PIQ scores. Prolonged use may impair non-verbal abilities reflected in PIQ, thereby compromising overall cognitive function - highlighting a critical clinical safety concern. By synthesizing current clinical observations and molecular mechanisms, this paper proposes that chloral hydrate may disrupt neurodevelopment through pathways including N-methyl-D-aspartate (NMDA) receptors, γ-aminobutyric acid (GABA) receptors, and the Mitogen-Activated Protein Kinase-Extracellular Signal-Regulated Kinase (MEK-ERK) signaling pathway. Basing on these findings, caution should be exercised regarding the use of chloral hydrate - particularly its long-term administration. Long-term follow-up of exposed children is recommended to continuously monitor cognitive function and neurodevelopment, with a focus on non-verbal abilities and overall intellectual development. Future research should prioritize prospective, long-term neurodevelopmental follow-up studies, specifically in children exposed to chloral hydrate, combined with neuroimaging and biomarker studies, to further explore its potential effects on neurodevelopment. In summary, this article synthesizes existing evidence to elucidate the effects of chloral hydrate on the developing brain, spanning clinical observations to underlying molecular mechanisms, with the aim of clarifying its potential implications for pediatric neurodevelopment.Keywords: chloral hydrate, developing brain, neuronal apoptosis, outpatient sedation, pediatric