Pharmacokinetics-based management of newborns affected by hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia

Perinatal asphyxia (PA) is caused by reduced blood flow or oxygen levels around the time of birth. Neonatal hypoxic-ischemic encephalopathy (HIE) specifically refers to the neurological damage resulting from PA and ischemia and is the most frequent cause of mortality and morbility in newborns. Therapeutic hypothermia (TH) is nowadays the standard of care to treat newborns with hypoxic-ischemic encephalopathy (HIE). However, pharmacokinetic (PK) changes during TH can impact the efficacy and safety of administered drugs. In this narrative review, we critically examined the main PK changes that occur during TH, focusing on alterations in drug distribution, metabolism and elimination. Hypothermia slows hepatic metabolism, reducing the clearance of some drugs and prolonging their half-life, while reduced tissue perfusion can alter drug distribution. Additionally, TH can affect protein binding of drugs and their ability to cross the blood-brain barrier, with significant implications for the management of seizures, sedation and antibiotic therapy. This review analyzes the available evidence on PK changes for drugs commonly used during TH, such as sedatives, analgesics and antibiotics and discusses the clinical implications for dose personalization and the management of side effect risks. Finally, future research areas are proposed to optimize pharmacological treatment in patients undergoing TH.