Neuroprotective therapies in the NICU in term infants: present and future

Abstract

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30–50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. Impact The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30–50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE.

Neonatal Hypoxic-Ischemic Encephalopathy and Hypothermia Treatment

“…The observed success with hypothermia has quickened the pace of laboratory investigations to identify viable pharmacologic therapies to justify randomized clinical trials and, ultimately, combine them with hypothermia. 76 Implementation of hypothermia has led to the identification of components of supportive care that may affect early childhood outcomes (hypoglycemia and hyperglycemia, hypocarbia, and blood pressure support) and require prospective investigation. With the dissemination of hypothermia, comprehensive organizations such as HOPE for HIE (https://www.hopeforhie.org, accessed May 5, 2023) have emerged to provide support and resources for parents of affected neonates.…”

Therapeutic Hypothermia Attenuates Cortical Interneuron Loss after Cerebral Ischemia in Near-Term Fetal Sheep

“…Therapeutic hypothermia is the only approved treatment for term infants with moderate to severe HIE and can improve survival and reduce disability when started within 6 h and continued for 72 h after injury [ 1 , 24 , 25 , 26 , 27 ]. Nevertheless, 30–50% of these infants treated with therapeutic hypothermia still die or experience significant disability [ 24 , 28 , 40 ]. A key finding of the present study was that all interneuron populations were protected with this standard clinical cooling protocol, suggesting that any persisting functional deficits in cooled infants may be unrelated to cortical interneuron survival.…”

Human chorionic gonadotropin decreases cerebral cystic encephalomalacia and parvalbumin interneuron degeneration in a pro-inflammatory model of mouse neonatal hypoxia-ischemia

“…Therefore, neuroprotective therapies that target the negative inflammatory actions contributing to newborn brain injury may offer added therapeutic benefit in newborns affected by HI and/or exposed to pro-inflammatory conditions that further augment the degree of cerebral injury. Indeed, recent research efforts have explored treatments that target the dysregulated immune response observed in perinatal brain injury with varying levels of success, as it is the case with agents such as erythropoietin, stem cells and melatonin (Molloy et al, 2022; Pedroza-Garcia et al, 2022).…”