Therapeutic hypothermia in newborns: evidence-based guidelines from a systematic review

Hypoxic-ischemic encephalopathy represents a major cause of neonatal mortality and long-term neurodevelopmental impairment. Therapeutic hypothermia has become the standard of care, significantly improving survival and outcomes. Nevertheless, its clinical implementation often lacks a standardized operational framework to ensure consistent efficacy and safety. The present work aimed to develop GRADE-based operational guidelines for therapeutic hypothermia, offering neonatologists a structured approach for identifying, treating, and monitoring newborns throughout the procedure. A panel of experts appointed by the Italian Society of Neonatology conducted a systematic review (PROSPERO registration CRD420250651303) of randomized controlled trials evaluating the effects of therapeutic hypothermia on neurodevelopmental outcomes. Literature searches were performed across Medline, Cochrane, Scopus, Embase, and Web of Knowledge databases, and studies were assessed using the Cochrane Risk-of-Bias 2 tool. Recommendations were formulated through consensus meetings following GRADE methodology and subsequently validated by an external multidisciplinary panel. Eight randomized controlled trials, encompassing a total of 1,843 newborns, met the inclusion criteria. Based on a comprehensive evaluation of study indications, characteristics, and outcomes, evidence-based recommendations were established. The risk-of-bias assessment revealed an even distribution between studies categorized as low and moderate risk. The resulting guidelines present a structured protocol covering all phases of therapeutic hypothermia - timing, clinical setting, management, and follow-up - and include proposals for expanding its application. To facilitate clinical implementation, the guidelines are accompanied by summary tables, graphical flowcharts, and algorithms designed for immediate use in neonatal intensive care settings. The GRADE-based recommendations presented here, now adopted as the Italian national clinical guidelines for therapeutic hypothermia in newborns, provide an evidence-driven and standardized framework to optimize neonatal care. These guidelines are intended to support daily clinical decision-making and will undergo periodic updates to incorporate emerging evidence and maintain their clinical relevance.