Pathophysiology Of Hypoxic-ischemic Encephalopathy Research Articles

Neuroprotective treatment options for neonatal hypoxic-ischemic encephalopathy: Therapeutic hypothermia and beyond

Hypoxic-ischemic encephalopathy (HIE) is the most common form of neonatal encephalopathy that develops due to perinatal asphyxia or ischemia in term and late-preterm infants. It is an important cause of significant neurological impairment and also mortality in newborns worldwide. The pathophysiology of HIE is multifactorial and involves complex cascades of cellular and biochemical events in the brain including excitotoxicity, oxidative stress, inflammation, and cell death, respectively. Therapeutic hypothermia (TH), is the only standard neuroprotective therapy for HIE and is associated with reduced composite outcome of death or major neurodevelopmental disability. However, although TH is beneficial, neonates with HIE still experience unacceptably high rate of devistating morbidities. Therefore, research for adjunctive therapies continue to further improve outcomes in infants with HIE. In this review, both TH and other promising adjunctive neuroprotective therapies are discussed for developing future treatment strategies.

Does MgSO4 protect the preterm brain? Dissecting its role in the pathophysiology of hypoxic ischemic encephalopathy.

Does MgSO4 protect the preterm brain? Dissecting its role in the pathophysiology of hypoxic ischemic encephalopathy.

Neuroprotective strategies of cerebrolysin for the treatment of infants with neonatal hypoxic-ischemic encephalopathy.

Perinatal asphyxia (PA) is a devastating neonatal condition characterized by a lack of oxygen supporting the organ systems. PA can lead to hypoxic-ischemic encephalopathy (HIE), a brain dysfunction due to oxygen deprivation with a complex neurological sequela. The pathophysiology of HIE and PA is not entirely understood, with therapeutic hypothermia being the standard treatment with only limited value. However, alternative neuroprotective therapies can be a potential treatment modality. In this review, we will characterize the biochemical mechanisms of PA and HIE, while also giving insight into cerebrolysin, a neuroprotective treatment used for HIE and PA. We found that cerebrolysin has up to 6-month treatment window post-ischemic insult. Cerebrolysin injections of 0.1ml/kg of body weight twice per week were found to provide gross motor and speech deficit improvement. Our literature search emphasizes the positive effects of cerebrolysin for general improvement outcomes. Nevertheless, biomarker establishment is warranted to improve patient outcomes.

Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy.

Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy.

Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future.

Hypoxic-ischemic encephalopathy, also referred as HIE, is a type of brain injury or damage that is caused by a lack of oxygen to the brain during neonatal period. The incidence is approximately 1.5 cases per 1000 live births in developed countries. In low and middle-income countries, the incidence is much higher (10‒20 per 1000 live births). The treatment for neonatal HIE is hypothermia that is only partially effective (not more than 50% of the neonates treated achieve an improved outcome). HIE pathophysiology involves oxidative stress, mitochondrial energy production failure, glutaminergic excitotoxicity, and apoptosis. So, in the last years, many studies have focused on peptides that act somewhere in the pathway activated by severe anoxic injury leading to HIE. This review describes the pathophysiology of perinatal HIE and the mechanisms that could be the target of innovative HIE treatments.

Inhaled Gases for Neuroprotection of Neonates: A Review.

Importance: Hypoxic-ischemic encephalopathy (HIE) is a significant cause of morbidity and mortality in neonates. The incidence of HIE is 1–8 per 1,000 live births in developed countries. Whole-body hypothermia reduces the risk of disability or death, but 7 infants needed to be treated to prevent death or major neurodevelopmental disability. Inhalational gases may be promising synergistic agents due to their rapid onset and easy titratability.Objective: To review current data on different inhaled gases with neuroprotective properties that may serve as adjunct therapies to hypothermia.Evidence review: Literature review was performed using the PubMed database, google scholar, and ClinicalTrials.Gov. Results focused on articles published from January 1, 2005, through December 31, 2017. Articles published earlier than 2005 were included when appropriate for historical perspective. Our review emphasized preclinical and clinical studies relevant to the use of inhaled agents for neuroprotection.Findings: Based on the relevance to our topic, 111 articles were selected pertaining to the incidence of HIE, pathophysiology of HIE, therapeutic hypothermia, and emerging therapies for hypoxic-ischemic encephalopathy in preclinical and clinical settings. Supplemental tables summarizes highly relevant 49 publications that were included in this review. The selected publications emphasize the emergence of promising inhaled gases that may improve neurologic survival and alleviate neurodevelopmental disability when combined with therapeutic hypothermia in the future.Conclusions: Many inhaled agents have neuroprotective properties and could serve as an adjunct therapy to whole-body hypothermia. Inhaled agents are ideal due to their easy administration, titrability, and rapid onset and offset.

Changes in bilirubin in infants with hypoxic-ischemic encephalopathy.

Antioxidant properties of bilirubin have been reported in many studies. We hypothesized that bilirubin might be involved in neuroprotection mechanisms against oxidative stress in infants with hypoxic-ischemic encephalopathy (HIE) and that total serum bilirubin (TSB) might increase in these patients. We retrospectively studied infants with gestational age ≥ 35weeks and birth weight ≥ 1800g who were admitted to the neonatal intensive care unit (NICU) with a diagnosis of moderate-to-severe HIE and received or did not receive therapeutic hypothermia. We evaluated peak TSB and changes of mean TSB in these patients in comparison with a control group of infants admitted to the NICU with diagnoses other than HIE. Peak and mean TSB values were lower in the no hypothermia and hypothermia groups in comparison with the control group, while differences were not noted between infants who received hypothermia or did not. Regression analysis showed that HIE and hypothermia significantly reduced the risk of developing TSB values higher than median value (> 8.4mg/dL) in our population.Conclusion: Peak and mean TSB values were lower in infants with moderate-to-severe HIE than in control infants. HIE and hypothermia independently decreased TSB. These results exclude a TSB increase as a neuroprotective mechanism in infants with HIE. We speculated that low TSB values in infants with HIE could be due to hypoxic repression of HO expression and represent a defensive strategy for limiting brain injuries in these patients. What is Known: • The role of oxidative stress in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) has been elucidated in many studies, and other studies have demonstrated the antioxidant properties of bilirubin. • The potential neuroprotective role of bilirubin as antioxidant agent has never been evaluated in infants with HIE. What is New: • Mean total serum bilirubin (TSB) values are lower in infants with moderate-to-severe HIE than in control infants, since HIE and hypothermia independently decreased TSB. • An increase in bilirubin was not a neuroprotective mechanism in infants with HIE possibly because of hypoxic repression of HO expression as defensive strategy for limiting brain injuries.

Regional differences of hypothermia on oxidative stress following hypoxia-ischemia: a study of DHA and hypothermia on brain lipid peroxidation in newborn piglets.

Background Oxidative stress plays an important part in the pathophysiology of hypoxic-ischemic encephalopathy (HIE) and is reliably measured through prostanoids following lipid peroxidation of polyunsaturated fatty acids (PUFAs). The aim of the study is to measure oxidative stress in the prefrontal cortex, white matter and hippocampus in the brains of hypoxic-ischemic piglets treated with docosahexaenoic acid (DHA) and therapeutic hypothermia (TH) and investigate the additive effects of DHA on hypothermia by factorial design. Methods Fifty-five piglets were randomized as having severe global hypoxia (n=48) or not (sham, n=7). Hypoxic piglets were further randomized: vehicle (VEH), DHA, VEH+hypothermia (HT) or HT+DHA. A total of 5 mg/kg DHA was given intravenously 210 min after the end of hypoxia. Brain tissues were analyzed using liquid chromatography triple quadrupole mass spectrometry technique (LC-MS). A two-way analysis of variance (ANOVA) was performed with DHA and HT as main effects. Results In the white matter, we found main effects of DHA on DH-isoprostanes (P=0.030) and a main effect of HT on F4-neuroprostanes (F4-NeuroPs) (P=0.007), F2-isoprostanes (F2-IsoPs) (P=0.043) and DH-isoprostanes (P=0.023). In the cortex, the ANOVA analysis showed the interactions of main effects between DHA and HT for neurofuranes (NeuroFs) (P=0.092) and DH-isoprostanes (P=0.015) as DHA significantly reduced lipid peroxidation in the absence of HT. DHA compared to VEH significantly reduced NeuroFs (P=0.019) and DH-isoprostanes (P=0.010). No differences were found in the hippocampus. Conclusion After severe hypoxia, HT reduced lipid peroxidation in the white matter but not in the cortical gray matter. HT attenuated the reducing effect of DHA on lipid peroxidation in the cortex. Further studies are needed to determine whether DHA can be an effective add-on therapy for TH.

Chapter 32 - Neurology of cardiopulmonary resuscitation

This chapter aims to provide an up-to-date review of the science and clinical practice pertaining to neurologic injury after successful cardiopulmonary resuscitation. The past two decades have seen a major shift in the science and practice of cardiopulmonary resuscitation, with a major emphasis on postresuscitation neurologic care. This chapter provides a nuanced and thoughtful historic and bench-to-bedside overview of the neurologic aspects of cardiopulmonary resuscitation. A particular emphasis is made on the anatomy and pathophysiology of hypoxic-ischemic encephalopathy, up-to-date management of survivors of cardiopulmonary resuscitation, and a careful discussion on neurologic outcome prediction. Guidance to practice evidence-based clinical care when able and thoughtful, pragmatic suggestions for care where evidence is lacking are also provided. This chapter serves as both a useful clinical guide and an updated, thorough, and state-of-the-art reference on the topic for advanced students and experienced practitioners in the field.

Analysis of the Mechanism of the pH-Dependent Shift in Substrate Affinity of ASCT1 Using Site-Directed Mutagenesis: Implications in the Pathophysiology of Hypoxic Ischemic Encephalopathy (HIE)

Analysis of the Mechanism of the pH-Dependent Shift in Substrate Affinity of ASCT1 Using Site-Directed Mutagenesis: Implications in the Pathophysiology of Hypoxic Ischemic Encephalopathy (HIE)

Perinatal hypoxic-ischemic brain injury: Maturation-dependent relation to epilepsy

There is clinical and experimental evidence that the response to hypoxic and hypoxic-ischemic brain injury is age dependent. The effects of perinatal hypoxia, especially its epileptogenic effects, are different in the neonatal brain compared with that of the adult. Experimental models show increased susceptibility of the immature brain to the epileptogenic and toxic effects of hypoxia and hypoxia-ischemia. This article reviews several maturational factors that are likely to contribute to the enhanced vulnerability of the immature brain. Some of the factors known to be involved in the pathophysiology of hypoxic-ischemic encephalopathy are also known to be critical for normal brain development. These issues are discussed in the context of defining age-specific therapies to prevent hypoxic-ischemic neuronal injury in the immature brain. MRDD Research Reviews 3:85–95, 1997. © 1997 Wiley-Liss, Inc.

Perinatal hypoxic‐ischemic brain injury: Maturation‐dependent relation to epilepsy

There is clinical and experimental evidence that the response to hypoxic and hypoxic-ischemic brain injury is age dependent. The effects of perinatal hypoxia, especially its epileptogenic effects, are different in the neonatal brain compared with that of the adult. Experimental models show increased susceptibility of the immature brain to the epileptogenic and toxic effects of hypoxia and hypoxia-ischemia. This article reviews several maturational factors that are likely to contribute to the enhanced vulnerability of the immature brain. Some of the factors known to be involved in the pathophysiology of hypoxic-ischemic encephalopathy are also known to be critical for normal brain development. These issues are discussed in the context of defining age-specific therapies to prevent hypoxic-ischemic neuronal injury in the immature brain. MRDD Research Reviews 3:85–95, 1997. © 1997 Wiley-Liss, Inc.