Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of death and long-term neurodevelopmental disorders in full-term neonates, and there is currently no curative treatment. Therapeutic hypothermia is now a standard therapy for HIE in the neonatal intensive care unit, but its safety and efficacy in remote areas remains unclear. Melatonin is an indole endocrine hormone mainly produced by the pineal gland and it has the ability to easily penetrate the blood-brain barrier. Through receptor and non-receptor mechanisms, melatonin exerts anti-oxidative and anti-inflammatory effects and participates in the regulation of organelle function and the inhibition of cell death. Melatonin is considered one of the most promising drugs for the treatment of HIE based on its reliable safety profile and clinical/preclinical results. This article reviews the recent research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal HIE.
Infant, Newborn ; Humans ; Melatonin/therapeutic use* ; Hypoxia-Ischemia, Brain/therapy* ; Hypothermia, Induced ; Intensive Care Units, Neonatal

Targeted temperature management (TTM) has been partially applied in patients with restoration of spontaneous circulation (ROSC) after cardiac arrest (CA). In the 2020 American Heart Association (AHA) cardiopulmonary resuscitation (CPR) guidelines, TTM is used as advanced life support after ROSC for the treatment of patients with CPR. TTM has a protective effect on cardiac function after CA, but the specific mechanism of its protective effect on cardiac function remains unclear. In this paper, the basic experimental progress, clinical trial progress and development prospect of TTM on the protective mechanism of cardiac function after CA are reviewed.
United States ; Humans ; Cardiopulmonary Resuscitation/methods* ; Temperature ; Heart Arrest/therapy* ; Hypothermia, Induced/methods* ; Body Temperature

Neonatal hypoxic-ischemic encephalopathy (HIE) is a common disease that affects brain function in neonates. At present, mild hypothermia and hyperbaric oxygen therapy are the main methods for the treatment of neonatal HIE; however, they are independent of each other and cannot be combined for synchronous treatment, without monitoring of brain function-related physiological information. In addition, parameter setting of hyperbaric oxygen chamber and mild hypothermia mattress relies on the experience of the medical practitioner, and the parameters remain unchanged throughout the medical process. This article proposes a new device for the treatment of neonatal HIE, which has the modules of hyperbaric oxygen chamber and mild hypothermic mattress, so that neonates can receive the treatment of hyperbaric oxygen chamber and/or mild hypothermic mattress based on their conditions. Meanwhile, it can realize the real-time monitoring of various physiological information, including amplitude-integrated electroencephalogram, electrocardiogram, and near-infrared spectrum, which can monitor brain function, heart rate, rhythm, myocardial blood supply, hemoglobin concentration in brain tissue, and blood oxygen saturation. In combination with an intelligent control algorithm, the device can intelligently regulate parameters according to the physiological information of neonates and give recommendations for subsequent treatment.
Infant, Newborn ; Humans ; Hypothermia, Induced/methods* ; Hypothermia/therapy* ; Hyperbaric Oxygenation ; Brain ; Electroencephalography ; Hypoxia-Ischemia, Brain/therapy*

OBJECTIVES: To investigate the clinical efficacy of mild therapeutic hypothermia (MTH) with different rewarming time on neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: A prospective study was performed on 101 neonates with HIE who were born and received MTH in Zhongshan Hospital, Xiamen University, from January 2018 to January 2022. These neonates were randomly divided into two groups: MTH1 group (n=50; rewarming for 10 hours at a rate of 0.25°C/h) and MTH2 group (n=51; rewarming for 25 hours at a rate of 0.10°C/h). The clinical features and the clinical efficacy were compared between the two groups. A binary logistic regression analysis was used to identify the factors influencing the occurrence of normal sleep-wake cycle (SWC) on amplitude-integrated electroencephalogram (aEEG) at 25 hours of rewarming. RESULTS: There were no significant differences between the MTH1 and MTH2 groups in gestational age, 5-minute Apgar score, and proportion of neonates with moderate/severe HIE (P>0.05). Compared with the MTH2 group, the MTH1 group tended to have a normal arterial blood pH value at the end of rewarming, a significantly shorter duration of oxygen dependence, a significantly higher proportion of neonates with normal SWC on aEEG at 10 and 25 hours of rewarming, and a significantly higher Neonatal Behavioral Neurological Assessment score on days 5, 12, and 28 after birth (P<0.05), while there was no significant difference in the incidence rate of rewarming-related seizures between the two groups (P>0.05). There were no significant differences between the two groups in the incidence rate of neurological disability at 6 months of age and the score of Bayley Scale of Infant Development at 3 and 6 months of age (P>0.05). The binary logistic regression analysis showed that prolonged rewarming time (25 hours) was not conducive to the occurrence of normal SWC (OR=3.423, 95%CI: 1.237-9.469, P=0.018). CONCLUSIONS Rewarming for 10 hours has a better short-term clinical efficacy than rewarming for 25 hours. Prolonging rewarming time has limited clinical benefits on neonates with moderate/severe HIE and is not conducive to the occurrence of normal SWC, and therefore, it is not recommended as a routine treatment method.
Infant, Newborn ; Infant ; Child ; Humans ; Child, Preschool ; Prospective Studies ; Rewarming ; Hypoxia-Ischemia, Brain/therapy* ; Hypothermia, Induced/methods* ; Treatment Outcome ; Electroencephalography/methods*

Consensus ; Humans ; Hypothermia, Induced ; Hypoxia-Ischemia, Brain/therapy* ; Infant, Newborn

OBJECTIVE: To study the changes in hemodynamics during the induction stage of systemic mild hypothermia therapy in neonates with moderate to severe hypoxic-ischemic encephalopathy (HIE). METHODS: A total of 21 neonates with HIE who underwent systemic mild hypothermia therapy in the Department of Neonatology, Dongguan Children's Hospital Affiliated to Guangdong Medical University, from July 2017 to April 2020 were enrolled. The rectal temperature of the neonates was lowered to 34℃ after 1-2 hours of induction and maintained at this level for 72 hours using a hypothermia blanket. The impedance method was used for noninvasive hemodynamic monitoring, and the changes in heart rate (HR), mean arterial pressure (MAP), stroke volume (SV), cardiac output (CO), cardiac index (CI), and total peripheral resistance (TPR) from the start of hypothermia induction to the achievement of target rectal temperature (34℃). Blood lactic acid (LAC) and resistance index (RI) of the middle cerebral artery were recorded simultaneously. RESULTS: The 21 neonates with HIE had a mean gestational age of (39.6±1.1) weeks, a mean birth weight of (3 439±517) g, and a mean 5-minute Apgar score of 6.8±2.0. From the start of hypothermia induction to the achievement of target rectal temperature (34℃), there were significant reductions in HR, CO, and CI ( CONCLUSIONS The systemic mild hypothermia therapy may have a significant impact on hemodynamics in neonates with moderate to severe HIE, and continuous hemodynamic monitoring is required during the treatment.
Cardiac Output ; Child ; Hemodynamics ; Humans ; Hypothermia ; Hypoxia-Ischemia, Brain/therapy* ; Infant ; Infant, Newborn ; Vascular Resistance

Arterial Occlusive Diseases ; diagnostic imaging ; surgery ; therapy ; Basilar Artery ; diagnostic imaging ; pathology ; surgery ; Humans ; Hypothermia ; diagnostic imaging ; surgery ; therapy ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Thrombectomy

Neonatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and long-term neurodevelopmental disabilities. Although promising neuroprotective interventions have been studied, the current management of HI brain injury has been limited to supportive measures and induced hypothermia. In addition to engrafting, migrating toward the damage sites and differentiating into multiple lineages, multipotent neural stem/progenitor cells (NSPCs) also provide trophic/immunomodulatory factors and integrate into the host neurons upon implantation into an HI-injured brain. However, NSPC-based therapies have shown poor cell survival and integration, poor differentiation or restricted differentiation into the glial lineages. Furthermore, to achieve full functional recovery following brain injury, the optimization of cell therapy is needed to recapitulate the precise migration of stem cells to the region of interest and the neural rewiring present in the brain microenvironment. Therefore, the efficacy of NSPCs in the treatment of CNS injury is currently insufficient. Human NSPCs (hNSPCs) were isolated from the forebrain of an aborted fetus at 13 weeks of gestation with full parental consent and the approval of the Institutional Review Board of the Yonsei University College of Medicine. Here, to enhance the regenerative ability of hNSPCs in HI brain injury, cells were either pretreated with pharmacological agents or engineered to serve as vehicles for gene delivery. Furthermore, when combined with a poly (glycolic acid)-based synthetic scaffold, hNSPCs provide a more versatile treatment for neonatal HI brain injury. Finally, hNSPCs transfected with zinc-doped ferrite magnetic nanoparticles for controlling both cell migration and differentiation offer a simple and smart tool for cell-based therapies.
Aborted Fetus ; Brain Injuries ; Brain ; Cell Movement ; Cell Survival ; Cell- and Tissue-Based Therapy ; Ethics Committees, Research ; Genetic Therapy ; Humans ; Hypothermia, Induced ; Hypoxia-Ischemia, Brain ; Infant ; Infant Mortality ; Nanoparticles ; Neural Stem Cells ; Neurons ; Parental Consent ; Pregnancy ; Prosencephalon ; Stem Cells ; Translational Medical Research

BACKGROUND: Preterm infants have difficulty maintaining body temperature after birth. However, clinical guidelines advocate that neonatal body temperature should be maintained at 36.5°C–37.5°C. PURPOSE: We aimed to investigate the incidence of admission hypothermia in very low birth weight (VLBW) infants and to determine the association of admission temperature with in-hospital mortality and morbidities. METHODS: A cohort study using prospectively collected data involving 70 neonatal intensive care units (NICUs) that participate in the Korean Neonatal Network. From registered infants born between January 2013 and December 2015, 5,343 VLBW infants born at less than 33 weeks of gestation were reviewed. RESULTS: The mean admission temperature was 36.1°C±0.6°C, with a range of 31.9°C to 38.4°C. Approximately 74.1% of infants had an admission hypothermia of <36.5°C. Lower birth weight, intubation in the delivery room and Apgar score <7 at 5 minutes were significantly related to admission hypothermia. The mortality was the lowest at 36.5°C–37.5°C and adjusted odd ratios for all deaths increased to 1.38 (95% confidence interval [CI], 1.04–1.83), 1.44 (95% CI, 1.05–1.97) and 1.86 (95% CI, 1.22–2.82) for infants with admission temperatures of 36.0°C–36.4°C, 35.0°C–35.9°C, and <35.0°C, respectively. Admission hypothermia was also associated with high likelihoods of bronchopulmonary dysplasia, pulmonary hypertension, proven sepsis, pulmonary hemorrhage, air-leak, seizure, grade 3 or higher intraventricular hemorrhage and advanced retinopathy of prematurity requiring laser therapy. CONCLUSION: A large portion of preterm infants in Korea had hypothermia at NICU admission, which was associated with high mortality and several important morbidities. More aggressive interventions aimed at reducing hypothermia are required in this high-risk population.
Apgar Score ; Birth Weight ; Body Temperature ; Bronchopulmonary Dysplasia ; Cohort Studies ; Delivery Rooms ; Hemorrhage ; Hospital Mortality ; Humans ; Hypertension, Pulmonary ; Hypothermia ; Incidence ; Infant ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Intensive Care Units ; Intensive Care Units, Neonatal ; Intubation ; Korea ; Laser Therapy ; Mortality ; Parturition ; Pregnancy ; Prospective Studies ; Retinopathy of Prematurity ; Seizures ; Sepsis

Neonates have large inter-individual variability in pharmacokinetic parameters of many drugs due to developmental differences. The aim of this study was to investigate the factors affecting the pharmacokinetic parameters of drugs, which are commonly used in critically ill neonates. Factors that reflect physiologic maturation such as gestational age, postnatal age, postconceptional age, birth weight, and current body weight were correlated with pharmacokinetic parameters in neonates, especially preterm infants. Comorbidity characteristics affecting pharmacokinetics in critically ill neonates were perinatal asphyxia, hypoxic ischemic encephalopathy, patent ductus arteriosus (PDA), and renal dysfunction. Administration of indomethacin or ibuprofen in neonates with PDA was associated with the reduced clearance of renally excreted drugs such as vancomycin and amikacin. Therapeutic hypothermia and extracoporeal membrane oxygenation were influencing factors on pharmacokinetic parameters in critically ill neonates. Dosing adjustment and careful monitoring according to the factors affecting pharmacokinetic variability is required for safe and effective pharmacotherapy in neonatal intensive care unit.
Amikacin ; Asphyxia ; Birth Weight ; Body Weight ; Comorbidity ; Critical Illness* ; Drug Therapy ; Ductus Arteriosus, Patent ; Gestational Age ; Humans ; Hypothermia, Induced ; Hypoxia-Ischemia, Brain ; Ibuprofen ; Indomethacin ; Infant, Newborn* ; Infant, Premature ; Intensive Care, Neonatal ; Membranes ; Oxygen ; Pharmacokinetics ; Vancomycin