Supplementary Material for: Dexmedetomidine as a Promising Neuroprotective Sedoanalgesic in Neonatal Therapeutic Hypothermia: A Systematic Review and Meta-Analysis

Background: Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal mortality and neurodevelopmental disabilities. Therapeutic hypothermia (TH) is the standard of care, but optimized sedoanalgesic strategies remain critical. Dexmedetomidine shows promise as an alternative to traditional sedatives, but its role in this context remains systematically underexplored. Objective: This meta-analysis evaluates the safety and efficacy of dexmedetomidine in neonates undergoing TH for HIE. Methods: A systematic search of Medline, Scopus, EMBASE, WOS, ClinicalTrials, and Cochrane Library identified studies published from January 2014 to October 2024. Studies focusing on dexmedetomidine in neonatal TH with relevant outcomes were included. Selection followed PRISMA guidelines, with independent quality assessments. The protocol was registered in PROSPERO (CRD42024605817). Results are presented as meta-analyses or evidence-based discussions when pooling was unfeasible. Results: Seven studies involving 609 neonates were included: four cohort studies (n = 486) and three case series (n = 123). Dexmedetomidine provided comparable sedation to traditional agents (MD = -0.01 [-0.68 - 0.66], p = 0.99) and significantly reduced seizure risk (OR 0.31 [0.10 - 0.98], p < 0.05) with a non-inferior safety profile. Trends suggested shorter duration of mechanical ventilation and time to full enteral feeding. Substantial heterogeneity in dosing protocols highlights the need for standardization. Conclusions: Dexmedetomidine appears to be a safe and promising sedative in neonatal TH for HIE, with potential neuroprotective, respiratory, and gastrointestinal benefits. Despite limited evidence and the absence of randomized clinical trials, its non-inferior efficacy and safety warrant further exploration and urges the development of standardized dosing protocols.