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Hypoxic Ischemic Encephalopathy: Pathophysiology and Experimental Treatments
Abstract
Hypoxic ischemic encephalopathy (HIE) is a serious birth complication affecting full term infants: 40-60% of affected infants die by 2 years of age or have severe disabilities. The majority of the underlying pathologic events of HIE are a result of impaired cerebral blood flow and oxygen delivery to the brain with resulting primary and secondary energy failure. In the past, treatment options were limited to supportive medical therapy. Currently, several experimental treatments are being explored in neonates and animal models to ameliorate the effects of secondary energy failure. This review discusses the underlying pathophysiologic effects of a hypoxic-ischemic event and experimental treatment modalities being explored to manage infants with HIE. Further research is needed to better understand if the long-term impact of the experimental treatments and whether the combinations of experimental treatments can improve outcomes in infants with HIE.
... Epidemiologic data suggest an incidence rate of HIE of 2 to 3 per 1000 live births, representing 6-9% of all neonatal deaths and 21-23% of neonatal deaths in full-term infants. Approximately 25% of survivors suffer from severe neurological sequelae, including cerebral palsy, seizures, mental retardation, cognitive impairment and epilepsy [115,116]. HIE is primarily developed due to reduced cerebral blood flow and insufficient oxygen supply to the brain. The pathophysiological effects of the disease progress over time, making timely and effective treatment difficult. ...
... Apoptotic cell death typically occurs during a few days after the injury. In the secondary phase of energy failure, which begins 6-48 hours after the initial injury, mechanisms such as oxidative stress, excitotoxicity and inflammation contribute to further damage [116]. Oxidative stress especially affects the neonatal brain due to the low concentration of antioxidants and high oxygen consumption during the transition to neonatal life [117]. ...
... Oxidative stress especially affects the neonatal brain due to the low concentration of antioxidants and high oxygen consumption during the transition to neonatal life [117]. Understanding the mechanisms of primary and secondary energy disturbances is crucial for effective therapeutic interventions [116]. 9 Although therapeutic hypothermia has progressed as a neuroprotective therapy for neonates with HIE, it is associated with adverse neurodevelopmental outcomes in some infants, and its use in preterm infants is only appropriate from 35 weeks of gestation [118][119][120]. ...
Neonatal disorders, particularly those resulting from prematurity, pose a major challenge to health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects and mechanistic insights of EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic-ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes the evidence for the therapeutic potential of EVs, analyzes the evidence on their mechanisms of action, and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.
... Sodium enters cells followed by water causing cell edema, widespread depolarization, and cell death. Cell death and lysis cause the release of glutamate, an excitatory amino acid, which causes an increase in intracellular calcium influx and further cell death [7,8]. ...
... Prostanoids also play a role in the hypoxic-ischemic event: Stimulating prostanoid receptors may be neuroprotective and prevent cerebellar neuronal injury. A partial recovery with reperfusion happens 30 to 60 minutes after the hypoxic-ischemic event in a penumbra of the brain, depending on the length of reduced perfusion and the presence or absence of medical intervention [8,9]. ...
... This latent phase is characterized by neuroinflammation and the continuation of an activated apoptotic cascade. In neonates with moderate to severe HIE, the latent phase is followed by the secondary phase, also known as secondary energy failure [8]. ...
Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe form of neonatal brain damage caused by decreased cerebral blood flow and hypoxia and can cause various serious irreversible neurological sequelae. An early diagnosis of HIE is essential for subsequent treatment and prognosis. Caspase, a protease enzyme that has an essential role in the apoptosis of programmed cell death, is one of the promising biomarkers for diagnosing HIE. Caspase-3 is recognized for its activated proteolytic apoptosis role in cells responding to specific extrinsic or intrinsic inducers of this mode of cell death. Caspase-3 is activated within 1 to 3 hours after neonatal hypoxic-ischemia and is a principal executioner of apoptosis. The role of caspase-3 in apoptosis, pyroptosis, necroptosis, and autophagy might be more profound than its role in cell death. Such functions of caspase-3 require further exploration, however, as there are still many possibilities for its roles in clinical diagnosis and treatment.
... HIE affects both premature and full-term neonates, with a prevalence of approximately 1-4 per 1000 neonates in developed countries and~26 per 1000 neonates in developing countries. About 35% of neonates with HIE develop long-term neurodevelopmental sequelae, such as mental retardation, epilepsy, cerebral palsy, and learning disabilities, while 25% die within the first two years of life [2,3]. ...
... The extent of brain injury and the outcome of HIE depend on various factors, including the etiology, extent of hypoxia/ischemia, maturation phase of the brain, regional cerebral blood flow, and maternal diseases/factors affecting the fetus [2]. Based on the extent of brain damage and neurological sequelae determined by clinical examination (Sarnat staging or Thompson score), HIE is categorized into mild, moderate, and severe [4]. ...
... The primary phase is characterized by primary energy failure (phase duration; minutes), followed by a resolution period or latent phase [2]. In brief, the primary phase starts when supplies of nutrients (glucose) and oxygen are decreased due to reduced blood flow in the brain. ...
Neonatal hypoxic-ischemic encephalopathy (HIE) is a condition that results in brain damage in newborns due to insufficient blood and oxygen supply during or after birth. HIE is a major cause of neurological disability and mortality in newborns, with over one million neonatal deaths occurring annually worldwide. The severity of brain injury and the outcome of HIE depends on several factors, including the cause of oxygen deprivation, brain maturity, regional blood flow, and maternal health conditions. HIE is classified into mild, moderate, and severe categories based on the extent of brain damage and resulting neurological issues. The pathophysiology of HIE involves different phases, including the primary phase, latent phase, secondary phase, and tertiary phase. The primary and secondary phases are characterized by episodes of energy and cell metabolism failures, increased cytotoxicity and apoptosis, and activated microglia and inflammation in the brain. A tertiary phase occurs if the brain injury persists, characterized by reduced neural plasticity and neuronal loss. Understanding the cellular and molecular aspects of the different phases of HIE is crucial for developing new interventions and therapeutics. This review aims to discuss the pathophysiology of HIE, therapeutic hypothermia (TH), the only approved therapy for HIE, ongoing developments of adjuvants for TH, and potential future drugs for HIE.
... 6 to 48 h after the initial injury, the secondary energy failure phase occurs and lasts for days. During this phase, increased intracellular Ca 2+ concentration activates proteases and phospholipases and induces inflammation and oxidative stress (Allen and Brandon, 2011;Dixon et al., 2015). Subsequently, these changes lead to a cascade of harmful effects, including excitotoxicity, cellular apoptosis and necrosis, impaired cerebral oxidative metabolism, and events leading to cell death (Allen and Brandon, 2011;Dixon et al., 2015). ...
... During this phase, increased intracellular Ca 2+ concentration activates proteases and phospholipases and induces inflammation and oxidative stress (Allen and Brandon, 2011;Dixon et al., 2015). Subsequently, these changes lead to a cascade of harmful effects, including excitotoxicity, cellular apoptosis and necrosis, impaired cerebral oxidative metabolism, and events leading to cell death (Allen and Brandon, 2011;Dixon et al., 2015). However, different from the primary stage of energy depletion, secondary energy failure occurs without brain acidosis (Allen and Brandon, 2011;Dixon et al., 2015). ...
... Subsequently, these changes lead to a cascade of harmful effects, including excitotoxicity, cellular apoptosis and necrosis, impaired cerebral oxidative metabolism, and events leading to cell death (Allen and Brandon, 2011;Dixon et al., 2015). However, different from the primary stage of energy depletion, secondary energy failure occurs without brain acidosis (Allen and Brandon, 2011;Dixon et al., 2015). Moreover, when mitochondria are incapable of buffering Ca 2+ , electron leakage from the electron transport chain occurs spontaneously, followed by increased generation of ROS, causing lipid peroxidation of the inner mitochondrial membrane (Lu et al., 2015). ...
Neonatal hypoxic-ischemic encephalopathy (HIE) is the primary reason for neonatal mortality and prolonged disablement. Currently, hypothermia is the only approved clinical treatment available for HIE. However, hypothermia's limited therapeutic efficacy and adverse effects suggest an urgent need to advance our knowledge of its molecular pathogenesis and develop novel therapies. The leading cause of HIE is impaired cerebral blood flow and oxygen deprivation-initiated primary and secondary energy failure. Lactate was traditionally regarded as a marker of energy failure or a waste product of anaerobic glycolysis. Recently, the beneficial aspects of lactate as supplementary energy for neurons have been demonstrated. Under the conditions of HI, lactate supports various functions of neuronal cells, including learning and memory formation, motor coordination, and somatosensory. Furthermore, lactate contributes to the regeneration of blood vessels and has shown its beneficial effects on the immune system. This review first introduces the hypoxic or ischemic events-induced fundamental pathophysiological changes in HIE and then discusses the potential neuroprotective properties of lactate for the treatment and prevention of HIE. Finally, we discuss the possible protective mechanisms of lactate in the context of the pathological features of perinatal HIE. We conclude that exogenous and endogenous lactate exert neuroprotective effects in HIE. Lactate administration may be a potential approach to treating HIE injury.
... Significantly, NE may result in brain damage, which in the context of HIE is due to inadequate levels of oxygen and blood to the brain [23,24] . As a result of brain injury, patients may suffer from periods of apnea, seizures, cardiorespiratory failure, and even death [24,25] . Currently, hypothermia therapy stands as the sole acute treatment for neonates following HIE, offering some degree of neuroprotection [26,27] . ...
... Recent studies have reported that TRPM7 channel blockers [28,29] or ryanodine receptor inhibitor [30] can effectively mitigate brain damage and improve neurobehavior outcomes in mouse models of HIE. Nevertheless, as of now, there is no pharmacological solution available for clinical NE patients that would permit early prevention of the development of severe complications [25] . Following the current standard of care, survivors living with NE can develop long-term behavioral impairments, including motor disability [21,24,31] . ...
Cerebral palsy (CP), the most common motor disorder in early childhood, arises from neonatal brain injury. The potential role of neonatal encephalopathy (NE) as a risk factor for cerebral palsy has been postulated, yet a systematic examination of its clinical impact on cerebral palsy patients remains absent. This meta-analysis aims to delineate the incidence of commonly reported complications associated with cerebral palsy following NE compared to those without a history of NE. A systematic search of PubMed and Google Scholar yielded 424 studies, with 7 meeting the inclusion criteria. These studies reported at least one comparison of cerebral palsy symptoms between patients with or without NE and provided the corresponding case numbers for each group. Utilizing RevMan 5.4, we analyzed the data and assessed potential publication bias. Among the 7 studies included, we compared the characteristics of 117 patients with cerebral palsy with preceding NE to 287 without such antecedents. Significantly, the incidence of the spastic quadriplegic subtype of cerebral palsy was higher in patients with NE (odds ratio [OR]: 4.34, 95% confidence interval [CI]: 2.69 – 7.00, P < 0.00001). CP patients following NE exhibited a significantly increased incidence of severe communication difficulties (OR: 2.33, 95% CI: 1.32 – 4.10, P = 0.003), difficulty swallowing (OR: 2.50, 95% CI: 1.31 – 4.77, P = 0.005), and cognitive impairment (OR: 2.73, 95% CI: 1.45 – 5.13, P = 0.002). Children with cerebral palsy born following NE were more predisposed to the most severe spastic quadriplegic subtype and encountered significant comorbidities. It is essential to acknowledge the limitations of this study, primarily the small number of studies that separately reported cerebral palsy cases with or without NE. Nevertheless, these findings contribute valuable insights for a more accurate clinical prognosis and the prospective development of targeted treatments for specific complications associated with cerebral palsy in patients with NE.
... These deficits can account for attention deficit hyperactivity disorder characteristics, such as decreased attention and increased impulsivity and compulsivity 5,6 . Thus, HIE remains a severe clinical problem worldwide despite efforts to provide therapies to mitigate and even reverse brain injury 7,8 . Therapeutic strategies aim to enhance neurorestoration, block neuroinflammatory response, exert neuroprotection and stimulate neurogenesis during the HIE development. ...
... Cerebrolysin is a peptide mixture that mimics the action of neurotrophic factors as shown by clinical trials and experimental assays in neurodegenerative diseases, cerebral ischemia, and traumatic brain injuries. Cerebrolysin overcomes other therapeutic alternatives because of its ability to activate neuroprotection and repair mechanisms, including increased cell proliferation, neural survival, and neurogenesis [7][8][9][10][11] . Cerebrolysin has been tested as a therapeutic agent in adult patients suffering from brain stroke, showing beneficial effects on function and global outcomes in the early rehabilitation phase 12 . ...
Background: Hypoxic-ischemic encephalopathy (HIE) is a neurological condition that leads to motor disabilities and even death in neonates. Unfortunately, few therapeutic alternatives can contribute to brain recovery after HIE damage. Cerebrolysin is a neuropeptide mixture that performs neuroprotective and neurotrophic effects on injured brain tissue after systemic administration. Aims: This study evaluates the effects of the Cerebrolysin intraperitoneal administration, Methods:10 mL/kg; once a day for 7 days, since postnatal day 8 (PD8) to PD14 on the neonatal neurobehavior in an HIE rat model was administrated. Results: Cerebrolysin administration after a hypoxic-ischemic insult minimized brain damage and increased cellular viability. Furthermore, this neuroprotective effect lasted until adulthood, improving some motor abnormalities and reversing the long-term memory acquisition deficit caused by HIE. Conclusion: Repeated Cerebrolysin administration can reduce HIE Motor Disabilities and Reverses the Long-Term Memory Acquisition Deficit in neonatal rats safely and effectively.
... HIE occurs when a hypoxic ischemic perinatal event such as a cord prolapse or shoulder dystocia disrupts oxygen and glucose delivery to the brain which can lead to death or severe neurological disability. 2 Neonatal HIE is divided by severity into mild, moderate, and severe, with moderate and severe categories reported to have increased risk of mortality and severe disability such as intellectual disability and epilepsy compared to mild HIE. 3,4 In 2005, Shankaren et al reported decreased mortality and morbidity in neonates with HIE who underwent whole body therapeutic hypothermia. ...
Objective
Evaluate the changes in management and outcomes of Californian infants with hypoxic ischemic encephalopathy (HIE).
Study Design
Infants with HIE were identified from a California administrative birth cohort using ICD codes and divided into two epochs, Epoch 1 (2010–2015) and Epoch 2 (2016–2019). Risk ratios (RR) for therapeutic hypothermia (TH) in each epoch and their outcomes were calculated using log-linear regression.
Results
In this cohort, 4779 infants with HIE were identified. Incidence of HIE in California increased yearly from 0.5/1,000 California births to a peak of 1.5/1,000 births in 2018. The use of TH in infants with mild HIE increased in Epoch 2 compared to Epoch 1. There was no significant difference in outcomes between epochs for infants with mild HIE that received TH.
Conclusion
Significantly more infants with mild HIE received TH since 2015 in California, but no difference in outcomes was found for these patients.
... The pathophysiology of encephalopathy in HIE is complex but the overall result of the insult is cellular injury and death contributing to the long term sequalae of HIE such as cerebral palsy [13]. In univariable analyses, administration of bicarbonate in our cohort was associated with higher rates of abnormal MRI and death. ...
Objective
To determine the safety and effectiveness of sodium bicarbonate administration in the management of metabolic acidemia and short-term outcomes in neonates with hypoxic-ischemic encephalopathy (HIE).
Study design
Retrospective cohort study of neonates born at ≥35 weeks of gestation and receiving therapeutic hypothermia. Demographics, pH, lactate, base deficit, treatment, MRI findings, seizure incidence, death prior to discharge were collected.
Results
There was higher mortality (p = 0.010) and injury on MRI (p = 0.008)—primarily deep gray matter (p < 0.001) and cortical injury (p = 0.003)—in the bicarbonate group compared to controls in univariate analysis. The combined outcome of death or abnormal MRI was not significantly associated (OR 1.97, 95% CI 0.80–4.87, p = 0.141) with bicarbonate administration when adjusting for sex, 5-minute Apgar, and initial base deficit.
Conclusion
This study demonstrated association between bicarbonate use after HIE and negative short-term outcomes. Future prospective trials could overcome the treatment bias limitation demonstrated in this retrospective study.
... Fetal distress is a condition caused by intrauterine fetal hypoxia during late pregnancy or labor and is closely associated with changes in Fetal Heart Rate (FHR) signals [1]. Fetal distress can tragically lead to cerebral palsy or neonatal death via hypoxic-ischemic encephalopathy [2]. If fetal distress is not promptly identified and treated, the vital organs of the fetus can be harmed before delivery. ...
Fetal hypoxia is a condition characterized by a lack of oxygen supply in a developing fetus in the womb. It can cause potential risks, leading to abnormalities, birth defects, and even mortality. Cardiotocograph (CTG) monitoring is among the techniques that can detect any signs of fetal distress, including hypoxia. Due to the critical importance of interpreting the results of this test, it is essential to accompany these tests with the evolving available technology to classify cases of hypoxia into three cases: normal, suspicious, or pathological. Furthermore, Machine Learning (ML) is a blossoming technique constantly developing and aiding in medical studies, particularly fetal health prediction. Notwithstanding the past endeavors of health providers to detect hypoxia in fetuses, implementing ML and Deep Learning (DL) techniques ensures more timely and precise detection of fetal hypoxia by efficiently and accurately processing complex patterns in large datasets. Correspondingly, this review paper aims to explore the application of artificial intelligence models using cardiotocographic test data. The anticipated outcome of this review is to introduce guidance for future studies to enhance accuracy in detecting cases categorized within the suspicious class, an aspect that has encountered challenges in previous studies that holds significant implications for obstetricians in effectively monitoring fetal health and making informed decisions.
... TH improves outcomes in neonates with gestational age ≥ 36 + 0 weeks and above with moderate to severe HIE. However, many infants still die or experience severe disabilities after undergoing TH 3,6,9 . In Norway, TH was introduced in 2007 as a treatment option for neonates with moderate to severe HIE 2 . ...
... Hypoxic-ischemic encephalopathy (HIE): HIE is a severe neurological disorder in neonates due to severe oxygen deficiency that can develop into severe hypoxia during labor. In 2011, Allen et al. published a paper in which, among the possible treatments for this severe condition, the authors proposed the use of ECMO to ensure the provision of oxygenation and circulatory support to the fetus, allowing time for potential recovery and minimizing further neurological damage [25]. No further scientific evidence is available for this therapeutic strategy. ...
Extracorporeal membrane oxygenation (ECMO) is a cardiac or pulmonary function support system that is used in cases of refractory organ failure in addition to conventional treatment. Currently, Level I evidence is not yet available, which reflects improved outcomes with ECMO in pregnant women, the use in pregnancy should be indicated in selected cases and only in specialized centers. We searched articles in the most important scientific databases from 2009 until 31 December 2023 consulting also the site ClinicalTrials.com to find out about studies that have been recently conducted or are currently ongoing. We matched the combination of the following keywords: “ECMO and pregnancy”, “H1N1 and pregnancy”, “COVID-19 and pregnancy”, “ARDS and pregnancy”, “ECMO and pregnancy AND (cardiac arrest)”. We selected the following number of articles for each keyword combination: “ECMO and pregnancy” (665 articles); “ECMO and influenza H1N1” (384 articles); “pregnancy and influenza H1N1” (1006 articles); “pregnancy and ARDS” (2930 articles); “ECMO and pregnancy and ARDS and influenza H1N1” (24 articles); and “[ECMO and pregnancy AND (cardiac arrest)]” (74 articles). After careful inspection, only 43 papers fitted our scope. There are two types of ECMO: venous-venous (VV-ECMO) and venous-arterial (VA-ECMO). The first-one is necessary to cope with severe hypoxia: oxygen-depleted blood is taken from the venous circulation, oxygenated, and carbon dioxide removed from the extracorporeal circuit and returned to the same venous system. The VA-ECMO is a type of mechanical assistance to the circulatory system that allows to put the failing organ at rest by ensuring adequate oxygenation and systemic de-oxygenation, avoiding multi-organ failure. The main indications for ECMO support in pregnant women are cardiogenic shock, acute respiratory distress syndrome (ARDS), pulmonary embolism, and eclampsia. There are also fetal indications for ECMO, and they are fetal distress, hypoxic-ischemic encephalopathy (HIE), and twin-to-twin transfusion syndrome (TTTS). Until now, based on the outcomes of the numerous clinical studies conducted, ECMO has been shown to be a successful therapeutic strategy in cases where medical treatment has been unsuccessful. In well-selected pregnant patients, it appears to be safe and associated with a low risk of maternal and fetal complications. The aim of this review is to report the main properties of ECMO (VV and VA) and the indications for its use in pregnant women.
... Cerebral palsy (CP), one of the most severe clinical outcomes of HIE, is a debilitating, non-progressive disorder, mainly affecting the motor system and being strongly related to perinatal brain damage (Kuban and Leviton, 1994;Volpe, 2001;Nelson et al., 2003;Allen and Brandon, 2011). Cognitive deficits may arise in children who have undergone HIE, irrespective of the presence of motor deficiencies, although cognitive and neuromotor deficits have been strongly associated (Van Handel et al., 2007;Lee and Glass, 2021). ...
Perinatal hypoxia-ischemia represents a significant risk to CNS development, leading to high mortality rates, diverse damages, and persistent neurological deficits. Despite advances in neonatal medicine in recent decades, the incidence of HIE remains substantial. Motor deficits can manifest early, while cognitive impairments may be diagnosed later, emphasizing the need for extended follow-up. This review aims to explore potential candidates for therapeutic interventions for hypoxic-ischemic encephalopathy (HIE), with a focus on cognitive deficits. We searched randomized clinical trials (RCT) that tested drug treatments for HIE and evaluated cognitive outcomes. The results included studies on erythropoietin, melatonin, magnesium sulfate, topiramate, and a combination of vitamin C and ibuprofen. Although there are several indications of the efficacy of these drugs among animal models, considering neuroprotective properties, the RCTs failed to provide complete effectiveness in the context of cognitive impairments derived from HIE. More robust RCTs are still needed to advance our knowledge and to establish standardized treatments for HIE.
... The scientific explanation for this finding could be, primarily, in fact, asphyxia is followed by the renal system and the central nervous system as the most severely affected systems. The primary and secondary energy failure that frequently occurs as HIE progresses reduces the prognosis of asphyxiated infants and causes the emergence of various neurologic sequelae [26]. Second, management and care are frequently inadequate and ineffective when the neonate has multiple organ damage and prolonged hypoxia. ...
Background
Even though there have been inquiries into the survival rates of asphyxiated neonates in Africa, there is scarce data concerning the recovery duration for asphyxiated newborns in developing nations and the factors affecting this process. Consequently, the objective of this study is to ascertain the time it takes for asphyxiated neonates to recover and identify its predictors.
Methods
Conducting a retrospective follow-up investigation, the study took place at Debre Berhan Comprehensive Specialized Hospital from January 1st, 2020 to December 31st 2022, involving a sample size of 330. The analysis included the computation of the Kaplan-Meier survival curve, the log-rank test, and the median time. Additionally, a multivariable Cox proportional hazard regression model was employed to determine the survival status.
Results
in this study, among the 330 participants (100%), a total of 270(81.8%) successfully survived throughout the entire cohort. Predictors are independent of each other, affecting the time to recovery and survival of asphyxiated neonates, encompassed prolonged labor (AHR: 0.42 ,95%CI:0.21–0.81), normal birth weight (AHR:2.21 ,95% CI: 1.30–3.70),non-altered consciousness (AHR:2.52 ,CI:1.50–4.24) ,non-depressed moro reflex of the newborn (AHR:2.40 ,95%CI: 1.03–5.61), stage I HIE (AHR: 5.11 ,95% CI: 1.98–13.19) ,and direct oxygen administration via the nose (AHR: 4.18 ,95% CI: 2.21–7.89).
Conclusion
The duration for recovery seems to be slightly prolonged in comparison to other research findings. This underscores the significance of vigilant monitoring, early preventive interventions, and swift actions to avert the progression of infants to the most severe stage of HIE.
... The scientific explanation for this finding could be, primarily, in fact, asphyxia is followed by the renal system and the central nervous system as the most severely affected systems. The primary and secondary energy failure that frequently occurs as HIE progresses reduces the prognosis of asphyxiated infants and causes the emergence of various neurologic sequelae [26]. Second, management and care are frequently inadequate and ineffective when the neonate has multiple organ damage and prolonged hypoxia. ...
Background
Even though there have been inquiries into the survival rates of asphyxiated neonates in Africa, there is scarce data concerning the recovery duration for asphyxiated newborns in developing nations and the factors affecting this process. Consequently, the objective of this study is to ascertain the time it takes for asphyxiated neonates to recover and identify its predictors.
Methods
Conducting a retrospective follow-up investigation, the study took place at Debre Berhan Comprehensive Specialized Hospital from January 1 st , 2020 to December 31 st 2022, involving a sample size of 330. The analysis included the computation of the Kaplan-Meier survival curve, the log-rank test, and the median time. Additionally, a multivariable Cox proportional hazard regression model was employed to determine the survival status.
Results
in this study, among the 330 participants (100%), a total of 270(81.8%) successfully survived throughout the entire cohort. Predictors are independent of each other, affecting the time to recovery and survival of asphyxiated neonates, encompassed prolonged labor (AHR: 0.42, 95%CI:0.21-0.81), normal birth weight (AHR:2.21, 95% CI: 1.30-3.70),non-altered consciousness (AHR:2.52, CI:1.50-4.24), non-depressed moro reflex of the newborn (AHR:2.40, 95%CI: 1.03-5.61), stage I HIE (AHR: 5.11, 95% CI: 1.98-13.19), and direct oxygen administration via the nose (AHR: 4.18, 95% CI: 2.21-7.89).
Conclusion
The duration for recovery seems to be slightly prolonged in comparison to other research findings. This underscores the significance of vigilant monitoring, early preventive interventions, and swift actions to avert the progression of infants to the most severe stage of HIE.
... As a result of hypoxia/ischemia in the brain, brain edemas and inflammation occur, leading to hypoxic-ischemic encephalopathy (HIE) [22]. In forensic autopsy cases, HIE can be caused by multiple conditions, such as traumatic or chemical events, respiratory and cardiac arrest, asphyxiation, or obstruction of the cerebral or cervical vessels [23,24]. ...
The levels and potential role of prolactin (PRL) in the brain under conditions of acute systemic hypoxia were examined, focusing on the accumulation of PRL in cerebrospinal fluid (CSF) and its effects on neuronal activity and injury. The amount of PRL in the brain was investigated using brain tissues from forensic autopsy cases. We counted the number of neurites that formed in human primary neurons (HNs) after the addition of PRL. Furthermore, HNs supplemented with PRL or triiodothyronine (T3) were exposed to hypoxic conditions, and the dead cells were counted. The results showed correlations between brain PRL and CSF PRL levels. Additionally, PRL accumulation in the brain was observed in cases of asphyxia. In vitro experimental findings indicated increased neurite formation in the HNs treated with PRL. Moreover, both PRL and T3 demonstrated neuroprotective effects against hypoxia-induced neuronal cell death, with PRL showing stronger neuroprotective potential than T3. These results suggest that PRL accumulates in the brain during hypoxia, potentially influences neuronal activity, and exhibits neuroprotective properties against hypoxia-induced neuronal injury.
... Careful screening of infants is necessary to ensure safety with TMS. Many infants with perinatal brain injury will experience seizures and be prescribed anti-seizure medications, which can influence cortical excitability [1,47]. Metal devices and implants such as patent ductus arteriosus (PDA) clips, ventriculoperitoneal shunts, or mechanical ventilation may also be more common after perinatal brain injury [48]. ...
Introduction:
Single-pulse transcranial magnetic stimulation (TMS) has many applications for pediatric clinical populations, including infants with perinatal brain injury. As a noninvasive neuromodulation tool, single-pulse TMS has been used safely in infants and children to assess corticospinal integrity and circuitry patterns. TMS may have important applications in early detection of atypical motor development or cerebral palsy.
Areas covered:
The authors identified and summarized relevant studies incorporating TMS in infants, including findings related to corticospinal development and circuitry, motor cortex localization and mapping, and safety. This special report also describes methodologies and safety considerations related to TMS assessment in infants, and discusses potential applications related to diagnosis of cerebral palsy and early intervention.
Expert opinion:
Single-pulse TMS has demonstrated safety and feasibility in infants with perinatal brain injury and may provide insight into neuromotor development and potential cerebral palsy diagnosis. Additional research in larger sample sizes will more fully evaluate the utility of TMS biomarkers in early diagnosis and intervention. Methodological challenges to performing TMS in infants and technical/equipment limitations require additional consideration and innovation toward clinical implementation. Future research may explore use of noninvasive neuromodulation techniques as an intervention in younger children with perinatal brain injury to improve motor outcomes.
... Most underlying pathologic events of HIE are a result of impaired cerebral blood flow and oxygen delivery to the brain with resulting primary and secondary energy failures. 1 By the age of 2 years, up to 60% infants with HIE will die or have severe disabilities including mental retardation, epilepsy, and cerebral palsy (CP). 1,2 Neuroimaging with ultrasonography (US), computed tomography (CT) and magnetic resonance (MR) imaging has become increasingly valuable in the work-up of particularly MR imaging-has the potential to play a significant role in diagnosis and early intervention in case of HIE 3,4 . ...
Perinatal asphyxia is one of the leading causes of hypoxic-ischemic encephalopathy. In a developing country like Nepal, home delivery is the leading cause of perinatal asphyxia. Neuroimaging remains the diagnostic modality of choice. We present a case report of a 10-month-old infant who presented to the pediatric Outpatient department with complaints of being unable to hold his head and unable to sit without support. Detailed history, physical examination, and developmental assessment along with lab investigation flash visual evoked potentials and Magnetic Resonance Imaging of the brain was performed. Hypoxic ischemic injury has common five types of imaging patterns in neonates. There are a few imaging differentials to be considered while evaluating the case for hypoxic injury. Clinicians and radiologists must go hand in hand to narrow down the possibilities which can fasten the treatment thereby decreasing morbidity and mortality.
... The pathophysiological effects of hypoxic-ischemic "stroke" (as commonly termed in foreign sources) are intricate, unfolding gradually over a specific period, posing challenges for medical professionals in determining timely and appropriate treatment options [4]. Recent publications increasingly discuss energy deficits at the neuronal level in infants with asphyxia and hypoxic-ischemic encephalopathy [5]. Currently, options for the timely diagnosis and treatment of prematurely born children with perinatal CNS damage are limited. ...
Introduction. Premature infants often experience a heightened risk of brain damage, potentially leading to various disorders affecting motor, cognitive, behavioral, social, and sensory functions. The underlying pathological processes of hypoxic-ischemic central nervous system (CNS) injury predominantly stem from compromised cerebral blood flow and oxygen transport. Timely diagnosis and treatment options for prematurely born children with perinatal CNS damage remain limited. Nitric oxide, a universal regulator of physiological functions, plays a crucial role. Endothelial dysfunction, marked by the loss of the neurovascular protective functions of nitric oxide, could significantly contribute to the development of cognitive impairment in hypoxic-ischemic CNS damage. Objectives. The study aims to evaluate the specificities of nitrate metabolism indicators in premature infants with hypoxic-ischemic CNS lesions in the early neonatal period. This involves examining and comparing clinical indicators characterizing hemodynamics, as well as the levels of nitrites, nitrates, and nitrosothiols in urine among patients in the studied groups. Subjects and Methods. The study comprised 14 premature infants with hypoxic-ischemic CNS injury (main group), with a separate selection of 4 infants who did not survive during the neonatal period. The comparison group included 20 relatively healthy prematurely born children. Stratification was based on the results of a genetic study, specifically the determination of the rs61722009 polymorphism of the eNOS gene. The patients underwent routine clinical examinations, including blood pressure measurements, and assessments of nitrates, nitrites, and nitrosothiols in urine. Subgroups were identified as follows: 1st subgroup - 4bb (n=10), and 2nd subgroup - 4aa/4ab (n=10). Results. It was observed that newborns who did not survive had significantly lower systolic and diastolic blood pressure readings on the first day of life, in comparison to relatively healthy children in the two control subgroups (day 1 - p=0.018; p=0.027; p=0.036; p=0.053). Additionally, they exhibited lower heart rate indicators on the first day (p=0.001; p=0.002). However, overall, hemodynamic indicators in newborns with hypoxic-ischemic central nervous system damage did not show statistically significant differences from the corresponding indicators in relatively healthy children. The results indicate a significantly lower level of diuresis in children who died as a result of severe with hypoxic-ischemic central nervous system damage, probably due to the development of multiple organ failure immediately after birth. As a result, it was found that the levels of nitrites (p<0.001; p<0.0001) and nitrates (p<0.01; p<0.0001) were reduced in children with with hypoxic-ischemic central nervous system damage, compared to children in the control groups, regardless of genotype variant. While the level of nitrosothiols did not differ significantly, it was even much higher in children who did not survive, 3.55±0.39 vs 2.23±0.22; p=0.008. The differences found may indicate a disruption of the regulatory effect of nitric oxyde on vascular tone and the condition of neuroglia, particularly in children with hypoxic-ischemic central nervous system damage, as a result of its insufficient production, as well as insufficient mobilization from the depot due to nitrite and nitrate reductases. Conclusions. Hemodynamic patterns in children from the examined groups, except for those who did not survive, did not exhibit significant differences. The notably lower urine output in deceased children indicates the development of multiple organ failure due to severe hypoxia. In children with hypoxic-ischemic central nervous system damage, there is a reduction in the levels of nitrites and nitrates in urine compared to relatively healthy premature infants, while the level of nitrosothiols did not show significant differences and was even notably higher in children who did not survive. The outcome of studying the levels of nitrates, nitrites, and nitrosothiols in urine in a larger patient sample may lead to the development of an algorithm for early diagnosis and management, contingent on the severity of metabolic disorders resulting from hypoxia, considering the potential influence of nitric oxide on energy deficit and mitochondrial dysfunction.
... HIE is a condition where there is insufficient oxygen and blood flow to the brain, leading to neurological damage and long-term disabilities, including cognitive impairments and cerebral palsy. HIE typically manifests as hypoxic-ischemic encephalopathy, characterized by seizures, abnormal EEG activity, hypotonia, feeding difficulties, and altered consciousness [44][45][46][47]. The incidence of hypoxic-ischemic encephalopathy (HIE) is 2.5 per 1000 term live births and a higher incidence is observed in less developed countries ranging from 5.5 to 26.5 per 1000 live births [48]. ...
Intrapartum foetal hypoxia is related to long-term morbidity and mortality of the foetus and the mother. Foetal surveillance is extremely important to minimize the adverse outcomes arising from foetal hypoxia during labour. Several methods have been used in current clinical practice to monitor foetal well-being. For instance, biophysical technologies including cardiotocography, ST-analysis adjunct to cardiotocography, and Doppler ultrasound are used for intrapartum foetal monitoring. However, these technologies result in a high false-positive rate and increased obstetric interventions during labour. Alternatively, biochemical-based technologies including foetal scalp blood sampling and foetal pulse oximetry are used to identify metabolic acidosis and oxygen deprivation resulting from foetal hypoxia. These technologies neither improve clinical outcomes nor reduce unnecessary interventions during labour. Also, there is a need to link the physiological changes during foetal hypoxia to foetal monitoring technologies. The objective of this article is to assess the clinical background of foetal hypoxia and to review existing monitoring technologies for the detection and monitoring of foetal hypoxia. A comprehensive review has been made to predict foetal hypoxia using computational and machine-learning algorithms. The detection of more specific biomarkers or new sensing technologies is also reviewed which may help in the enhancement of the reliability of continuous foetal monitoring and may result in the accurate detection of intrapartum foetal hypoxia.
... Several factors, including the duration of cardiac arrest, the effectiveness of resuscitation efforts, and the underlying cause of the arrest influence the severity of the resultant brain injury. Recognizing the unique susceptibility of pediatric patients to global hypoxic-ischemic injury underscores the importance of tailored and vigilant post-resuscitation care to mitigate neurological consequences [28]. Secondary brain injury: In the post-resuscitation phase, efforts are concentrated on preventing or mitigating secondary brain injury. ...
This comprehensive review thoroughly examines post-resuscitation care in pediatric ICUs (PICUs) following cardiac arrest. The analysis encompasses adherence to resuscitation guidelines, advances in therapeutic interventions, and the nuanced management of neurological, cardiovascular, and respiratory considerations during the immediate post-resuscitation phase. Delving into the complexities of long-term outcomes, cognitive and developmental considerations, and rehabilitation strategies, the review emphasizes the importance of family-centered care for pediatric survivors. A call to action is presented, urging continuous education, research initiatives, and quality improvement efforts alongside strengthened multidisciplinary collaboration and advocacy for public awareness. Through implementing these principles, healthcare providers and systems can collectively contribute to ongoing advancements in pediatric post-resuscitation care, ultimately improving outcomes and fostering a culture of excellence in pediatric critical care.
... Neonatal encephalopathy is a condition with variable clinical expression including encephalopathy, hypotonia, apnea, seizures, and death [1,2]. Hypoxic ischemia in the perinatal period is the most commonly attributed cause, but genetic or metabolic causes are identified in some cases [3]. ...
Background:
Late preterm (LPT) infants are increasingly treated for hypoxic-ischemic encephalopathy (HIE). However, neurodevelopmental differences of LPT infants may independently influence the neurologic exam and confound care.
Methods:
Perinatal and outcome characteristics were extracted along with the worst autonomic and state/neuromuscular/reflex Sarnat components in a cross-section of infants with moderate/severe HIE. Infants were classified as late preterm (LPT, 34-36 weeks) or term (>36 weeks).
Results:
250 infants were identified, 55 were late preterm. LPT infants had lower mean gestational age and birthweight and greater length of stay (LOS). LPT infants had higher median scores for the Moro and respiratory autonomic components, but no difference in total score.
Conclusions:
LPT infants had increased LOS, worse Moro reflex, and respiratory status, but no clinically or statistically significant differences in total Sarnat scores. Although it is important to note the impact of immaturity on the exam, it is unlikely to independently alter management.
... Furthermore, the hypoxic chamber was wrapped in an electric blanket to maintain an internal temperature of 36°C. Excessively low temperatures should be crucially avoided, as they can alleviate HIBD (Allen and Brandon, 2011). After 2.5 h of hypoxia, the neonatal rats were removed from the chamber and returned to their cages for rearing. ...
Objective
This study aimed to investigate the effects of neonatal hypoxic–ischemic brain damage (HIBD) on early-stage neuro-motor function, cerebral blood flow, and the neurovascular unit.
Methods
Twenty-four Sprague–Dawley newborn rats aged 7 days were obtained and randomly assigned to either the sham or the model group using a random number table. The HIBD model was established using the Rice-Vannucci method. After the induction of HIBD, the body weight of the rats was measured and their neuro-motor function was assessed. Further, cerebral blood flow perfusion was evaluated using laser speckle flow imaging, and immunofluorescent staining techniques were employed for examining the activation of specific markers and their morphological changes in different cell populations, which included vascular endothelial cells, neurons, astrocytes, and microglia within the motor cortex.
Results
After HIBD, the model group exhibited impaired neuro-motor function and growth. Cerebral blood flow perfusion decreased in both the hemispheres on day 1 and in the ipsilateral brain on day 4. However, no significant difference was observed between the two groups on day 7. Moreover, the CD31 and NeuN showed a sharp decline on day 1, which was followed by a gradual increase in the expression levels. The activated microglia and astrocytes formed clusters in the injured cortex. Notably, the regions with positive staining for Arg-1, Iba-1, CD68, and GFAP consistently displayed higher values in the model group as compared to that in the sham group. The total number of branch endpoints and microglia branches was higher in the model group than in the sham group. Immunofluorescent co-localization analysis revealed no co-staining between Iba-1 and Arg-1; however, the Pearson’s R-value for the co-localization of Iba-1 and CD68 was higher in the model group, which indicated an increasing trend of co-staining in the model group.
Conclusion
Early-stage neuro-motor function, cerebral blood flow, microvasculature, and neurons in neonatal rats exhibited a trend of gradual recovery over time. The activation and upregulation of neuroglial cells continued persistently after HIBD. Furthermore, the impact of HIBD on early-stage neuro-motor function in newborn rats did not synchronize with the activation of neuroglial cells. The recovery of neuro-motor function, microvasculature, and neurons occurred earlier than that of neuroglial cells.
... Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide, with an incidence of between 1.0 and 8.0 per 1,000 live births (1). In those who survive there is an increased risk of long-term neurological morbidities, such as cerebral palsy, epilepsy, learning and behavioral problems (2). Mild therapeutic hypothermia is a standard of care in high income countries (3,4); however, up to 40-50% of infants treated with therapeutic hypothermia die or develop chronic neurological impairment (5). ...
Hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality. Although therapeutic hypothermia is an effective treatment, substantial chronic neurological impairment often persists. The long-chain omega-3 polyunsaturated fatty acids (PUFAs), docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, offer therapeutic potential in the post-acute phase. To understand how PUFAs are affected by HIE and therapeutic hypothermia we quantified for the first time the effects of HIE and therapeutic hypothermia on blood PUFA levels and lipid peroxidation. In a cross-sectional approach, blood samples from newborns with moderate to severe HIE, who underwent therapeutic hypothermia (sHIE group) were compared to samples from newborns with mild HIE, who did not receive therapeutic hypothermia, and controls. The sHIE group was stratified into cerebral MRI predictive of good (n = 10), or poor outcomes (n = 10; nine developed cerebral palsy). Cell pellets were analyzed for fatty acid content, and plasma for lipid peroxidation products, thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal. Omega-3 Index (% DHA + EPA) was similar between control and HIE groups; however, with therapeutic hypothermia there were significantly lower levels in poor vs. good prognosis sHIE groups. Estimated Δ-6 desaturase activity was significantly lower in sHIE compared to mild HIE and control groups, and linoleic acid significantly increased in the sHIE group with good prognosis. Reduced long-chain omega-3 PUFAs was associated with poor outcome after HIE and therapeutic hypothermia, potentially due to decreased biosynthesis and tissue incorporation. We speculate a potential role for long-chain omega-3 PUFA interventions in addition to existing treatments to improve neurologic outcomes in sHIE.
... In addition to a detrimental effect on cell viability, another hallmark and potential therapeutic target of HIE is excessive reactive gliosis, which leads to glial scar formation and impedes axon regeneration [46,47]. We have previously shown that PKN1 regulates axonal outgrowth via the inhibition of AKT signaling. ...
We recently identified protein kinase N1 (PKN1) as a negative gatekeeper of neuronal AKT protein kinase activity during postnatal cerebellar development. The developing cerebellum is specifically vulnerable to hypoxia-ischemia (HI), as it occurs during hypoxic-ischemic encephalopathy, a condition typically caused by oxygen deprivation during or shortly after birth. In that context, activation of the AKT cell survival pathway has emerged as a promising new target for neuroprotective interventions. Here, we investigated the role of PKN1 in an in vitro model of HI, using postnatal cerebellar granule cells (Cgc) derived from Pkn1 wildtype and Pkn1−/− mice. Pkn1−/− Cgc showed significantly higher AKT phosphorylation, resulting in reduced caspase-3 activation and improved survival after HI. Pkn1−/− Cgc also showed enhanced axonal outgrowth on growth-inhibitory glial scar substrates, further pointing towards a protective phenotype of Pkn1 knockout after HI. The specific PKN1 phosphorylation site S374 was functionally relevant for the enhanced axonal outgrowth and AKT interaction. Additionally, PKN1pS374 shows a steep decrease during cerebellar development. In summary, we demonstrate the pathological relevance of the PKN1-AKT interaction in an in vitro HI model and establish the relevant PKN1 phosphorylation sites, contributing important information towards the development of specific PKN1 inhibitors.
... However, the pathophysiological consequences of hypoxicischemic "stroke" (this is the term used in most foreign sources) are complex and develop gradually over a period of time, which makes it diffi cult for medical professionals to determine timely and adequate treatment options [9]. There is an increasing number of publications on energy defi cits at the neuronal level in infants with asphyxia and hypoxicischemic encephalopathy [10]. Currently, the options for timely diagnosis and treatment of premature infants with hypoxic lesions of the central nervous system are limited. ...
Metabolic syndrome is considered to be a cluster of disorders that directly contribute to the development of cardiovasculardisease and are characterized by chronic systemic infl ammation. Numerous epidemiological data indicate that an adverseintrauterine environment, caused by the peculiarities of the nutritional status or placental insuffi ciency in a woman with metabolic syndrome, can “program” the susceptibility of the fetus to further development of cardiovascular and metabolic diseases, has an impact on cognitive and behavioral development. Nitric oxide (NO) plays a critical role in the pathogenesis of components of the metabolic syndrome. Children born prematurely have a high incidence of brain damage, which can lead to motor, cognitive, behavioral, social and sensory disorders.The purpose the research was the study of the effect of the eNOS gene polymorphism and indicators of nitric oxidemetabolism on the neonatal consequences in prematurely born children from mothers with metabolic syndrome.Material and methods. A study was conducted in which 100 premature infants were included. Two groups were formed: the main group (n=34), which included preterm infants (birth weight 2145.29±148.19 g and gestational age 33.18±0.55 weeks) of mothers with metabolic syndrome, and the comparison group (n=66), which included preterm infants (birth weight 2295.99±101.45 and gestational age 34.03±0.45 weeks) of mothers without metabolic syndrome. The children underwent a genetic study – determination of the polymorphism of the eNOS gene, as well as the level of nitrites, nitrates and nitrosothiols in the urine.By decision of the bioethics commission No. 217 dated 12.06.2023, the materials of the scientifi c work comply with the Rulesof Humane Treatment of Patients.Traditional methods of parametric and nonparametric statistics were used; nonparametric methods were used to analyzequalitative characteristics expressed mainly in percentages. The methods of parametric statistics were used to check the normality of the distribution of quantitative characteristics using the Kolmogorov- Smirnov criterion.Statistical processing of the obtained results was carried out using the package of application programs EXCEL-2003® andSTATA version 11 for Windows (StataCorp, Texas, USA).The work was carried out as part of the scientifi c and experimental work of the Department of Pediatrics #1 with Neonatologyof the Poltava State Medical University “To develop clinical and laboratory criteria, methods of predicting and preventingmetabolic disoders in young children (state registration number 0120U102856).Results. The most common diseases in the infants of the studied groups were the consequences of intrauterine hypoxia(44.1%) and respiratory failure requiring artifi cial lung ventilation (50.0%), although no signifi cant diff erences were foundin the prevalence of these conditions. We identifi ed the presence of signifi cant associations between the consequences ofintrauterine hypoxia and the levels of nitrates (OR 1.19; 95% CI 1.01-1.40; p=0.042), nitrosothiols (OR 1.19; 95% CI 0.99-1.42;p=0.050) and the polymorphic genotype 4aa/ab of the eNOS gene (OR 0.28; 95% CI 0.12-0.67; p=0.004). Analysis of systemichemodynamics revealed no signifi cant diff erences in baseline values between preterm infants with and without intrauterinehypoxia, but we did observe an association with urine output on day 3 of life.To fi nally clarify the complex infl uence of indicators of nitrate metabolism on the development of intrauterine hypoxia andto predict the development of consequences of this condition in premature infants, the following indicators are included in theregression prognostic model: the level of nitrates, nitrites, 4aa/4ab genotype and urine output on the third day of life. As theresearch results show, there is a direct reliable relationship with nitrates and an inverse relationship with nitrites, 4aa/4abgenotype and urine output. This prediction model has high operating characteristics – the area under the ROC curve is 0.8168.Some mechanisms of the infl uence of maternal metabolic syndrome on the development of relevant disorders in newborns areknown, including disorders of nitric oxide synthesis, endothelial dysfunction, and oxidative stress. In our study, the consequences of intrauterine hypoxia were reliably associated with an increase in the concentration of urinary nitrates and a decrease in nitrites, as well as the absence of the 4aa/ab genotype, which is associated with reduced release of nitric oxide. There is evidence that nitric oxide can have both protective and deleterious eff ects, depending on factors such as nitric oxide synthase isoform and duration of exposure to hypoxia.Conclusions. In preterm infants born to mothers with metabolic syndrome, elevated urinary nitrate levels and the absenceof the eNOS 4aa/ab genotype increase the likelihood of suff ering the consequences of intrauterine hypoxia.
... Abnormal signal intensity in the cerebellum on DWIs have also been identified on qualitative assessment 16 . This damage may result from mechanisms such as cytotoxic oedema, inflammation, and cellular apoptosis, that can cause neuronal damage and restricted diffusion in neonates [41][42][43] . Additionally, neonatal studies have shown that cerebellar injury from HIE commonly occurs in conjunction with damage to other regions of the brain, including the BGT and brainstem 16,38 . ...
Children cooled for HIE and who did not develop cerebral palsy (CP) still underperform at early school age in motor and cognitive domains and have altered supra-tentorial brain volumes and white matter connectivity. We obtained T1-weighted and diffusion-weighted MRI, motor (MABC-2) and cognitive (WISC-IV) scores from children aged 6–8 years who were cooled for HIE secondary to perinatal asphyxia without CP (cases), and controls matched for age, sex, and socioeconomic status. In 35 case children, we measured cerebellar growth from infancy (age 4–15 days after birth) to childhood. In childhood, cerebellar volumes were measured in 26 cases and 23 controls. Diffusion properties (mean diffusivity, MD and fractional anisotropy, FA) were calculated in 24 cases and 19 controls, in 9 cerebellar regions. Cases with FSIQ ≤ 85 had reduced growth of cerebellar width compared to those with FSIQ > 85 (p = 0.0005). Regional cerebellar volumes were smaller in cases compared to controls (p < 0.05); these differences were not significant when normalised to total brain volume. There were no case–control differences in MD or FA. Interposed nucleus volume was more strongly associated with IQ in cases than in controls (p = 0.0196). Other associations with developmental outcome did not differ between cases and controls.
... The removal of lactate after HI insults in neonates produces more brain damage, while the addition of glucose had no additive effect. Multiple interparietal injections of lactate following HI insult led to full recovery of long-term memory, sensorimotor abilities and neurological reflexes [50,51]. Lactate can act as a signaling molecule, and recent studies have shown that lactate can bind to a receptor called HCAR1 (hydroxycarboxylic acid receptor), previously referred to as GPR81 (G-protein-coupled receptor 81), in human and rodent brains [52,53]. ...
Neural tissue requires a great metabolic demand despite negligible intrinsic energy stores. As a result, the central nervous system (CNS) depends upon a continuous influx of metabolic substrates from the blood. Disruption of this process can lead to impairment of neurological functions, loss of consciousness, and coma within minutes. Intricate neurovascular networks permit both spatially and temporally appropriate metabolic substrate delivery. Lactate is the end product of anaerobic or aerobic glycolysis, converted from pyruvate by lactate dehydrogenase-5 (LDH-5). Although abundant in the brain, it was traditionally considered a byproduct or waste of glycolysis. However, recent evidence indicates lactate may be an important energy source as well as a metabolic signaling molecule for the brain and astrocytes—the most abundant glial cell—playing a crucial role in energy delivery, storage, production, and utilization. The astrocyte–neuron lactate-shuttle hypothesis states that lactate, once released into the extracellular space by astrocytes, can be up-taken and metabolized by neurons. This review focuses on this hypothesis, highlighting lactate’s emerging role in the brain, with particular emphasis on its role during development, synaptic plasticity, angiogenesis, and disease.
... Hypoxic ischaemic encephalopathy (HIE) is a serious birth complication resulting from impaired cerebral blood flow and oxygen delivery in term infants [1]. Treatment response and outcome prediction are measured using a combination of the results of clinical examination, amplitude integrated electroencephalography (aEEG) and magnetic resonance imaging (MRI) of the brain [2]. ...
Objectives:
Hypoxic ischaemic encephalopathy (HIE) is associated with oxidative stress. A potential marker of oxidative damage is carboxyhaemoglobin (COHb) which is the product of the reaction between carbon monoxide and haemoglobin and is routinely assessed on blood gas analysis. Our objective was to test the hypothesis that higher COHb levels would be associated with worse outcomes in infants treated for HIE.
Methods:
A retrospective, observational study was performed of all infants who received whole body hypothermia for HIE at a tertiary neonatal intensive care unit between January 2018 and August 2021. For each participating infant, the highest COHb level per day was recorded for days one, three and five after birth.
Results:
During the study period, 67 infants with a median (IQR) gestational age of 40 (38-41) weeks underwent therapeutic hypothermia for HIE. The median (IQR) COHb level on day three was higher in infants without electroencephalographic seizures (1.4 [1.1-1.4] %) compared with infants with seizures (1.1 [0.9-1.3] %, p=0.024). The median (IQR) COHb on day five was higher in infants without MRI brain abnormalities (1.4 [1.2-1.7] %) compared with infants with MRI abnormalities (1.2 [1.0-1.4] %, p=0.032). The COHb level was not significantly different between the nine infants who died compared to the infants who survived.
Conclusions:
COHb levels were higher in infants with HIE without seizures and in those with normal MRI brain examinations. We suggest that carbon monoxide has a potential protective role in HIE.
... HIE-like manifestations could be explained by the increased susceptibility toward hypoxic brain injury. Genetic abnormalities associated with the activation of cytokines, increased neuroinflammation, mitochondrial dysfunction, and activation of neuronal apoptosis [26] have been reported to be predisposing conditions toward brain hypoxia, irrespective of obvious hypoxic insults. ...
Partial deletion of the long arm (q) in chromosome 21 is an extremely rare condition with various phenotypes, including microcephaly, neurodevelopmental delay, dysmorphic features, and epileptic seizures. Neonatal hypoxic-ischemic encephalopathy (HIE) is an encephalopathy associated with a hypoxic-ischemic event in the brain where seizures usually occur in the earliest days of life. Neonatal encephalopathy is a distinct entity resulting from metabolic disorders, congenital infections or genetic abnormalities that could often mimic HIE features, leading to a misdiagnosis of HIE. Here, we present a case of a newborn who was initially misdiagnosed with HIE due to HIE-like features, and eventually was diagnosed to have a de novo ring chromosome 21 with 21q microdeletion. Clinical findings, including severe hypotonia with respiratory/feeding difficulties and intractable seizures, and radiologic findings of ischemic encephalopathy were discovered. Subsequent atypical findings of the clinical presentation ultimately led to her undergoing genetic testing confirming that she had a neonatal encephalopathy with a genetic abnormality. Our case highlights the importance of identifying non-HI neonatal encephalopathy by careful and structured evaluation for current history with a clinical course and a multidisciplinary approach including genetic testing, to provide an accurate diagnosis, treat curable inherited disorders, and develop future genetic counseling.
... Hypoxic-ischemic encephalopathy (HIE): HIE refers to brain injury in the newborn due to oxygen deprivation during birth. In severe cases, ECMO may be considered to provide oxygenation and circulatory support to the fetus, allowing time for potential recovery and minimizing further neurological damage [18]. ...
Extracorporeal membrane oxygenation (ECMO) is a life-saving technology that temporarily supports the heart and lungs in critical care situations. This review article examines the role of ECMO as a lifeline for pregnant and postpartum women facing severe maternal and fetal conditions. The review begins with an overview of the physiology and pathophysiology of ECMO, including its procedure and how it supports cardiopulmonary function. Unique considerations specific to pregnant and postpartum women, such as physiological changes during pregnancy, risks and complications associated with ECMO, and the need to balance maternal and fetal considerations, are discussed. The indications for ECMO in this population are explored, including common maternal indications such as cardiogenic shock, acute respiratory distress syndrome (ARDS), pulmonary embolism, and eclampsia, as well as fetal indications such as fetal distress, hypoxic-ischemic encephalopathy (HIE), and twin-to-twin transfusion syndrome (TTTS). The challenges and considerations in ECMO for pregnant and postpartum women, including ethical considerations and the decision-making process, are highlighted. The review further explores the multidisciplinary care and collaborative approach required, emphasizing the importance of a specialized ECMO team and collaboration between obstetricians, neonatologists, cardiologists, and other specialists. Additionally, patient selection, pre-ECMO assessment, and planning strategies are discussed. The review evaluates existing literature and studies on ECMO in pregnant and postpartum women, analyzing survival rates and maternal and fetal outcomes and comparing different ECMO modalities and strategies. Future directions and research opportunities are presented, including emerging technologies, areas for further research and clinical trials, and improved patient selection and management strategies. The conclusion emphasizes the importance of ECMO as a lifeline for pregnant and postpartum women and the potential impact on maternal and fetal health. The review highlights the need for ongoing research and advancements in ECMO to optimize outcomes and improve care for this unique and vulnerable patient population.
... Perinatal asphyxia leading to Hypoxic ischemic encephalopathy is a common problem causing multi organ dysfunction including myocardial involvement which can affect the outcome. Sometimes cardiac dysfunction may be so severe that it can cause congestive cardiac failure and shock that leads to death 2 in new born .HIE is marked by neonatal encephalopathy that is a sequela of systemic hypoxemia and decreased cerebral perfusion 3 which result in ischemia .Its incidence is reported to range from 1.5 to 4 2.5 per 1,000 live births in developed countries . In developing and underdeveloped countries its incidence has been reported to be much 5,6 higher ranging from 10 to 20 per 1,000 live births . ...
Introduction- WHO dene birth asphyxia as failure to initiate and sustain breathing at birth. Perinatal asphyxia leading to Hypoxic ischemic encephalopathy is a common problem causing multi organ dysfunction including myocardial involvement which can affect the outcome. Cardiac Troponin-I, a marker of myocardial injury, has been shown to be high in asphyxiated neonates as compared to healthy neonates. Moreover, it has also been reported to have an association with adverse outcomes and mortality. Cardiac troponin-I has been shown to be good predictors of HIE in neonates and has been shown to have a strong correlation with clinical grade of HIE. This prospectiv Material & Methods- e cohort study was conducted on patients admitted in NICU of Department of pediatrics of CIMSH, Lucknow. In our study(n=60), term asphyxiated neonates with APGAR <7 at 1min were included. -The total 60 asphyxiated neonates had HIE. Pre Result valence of HIE stage I, II and III was 43.3%, 25% and 31.7% respectively. Mean cardiac Troponin-I levels were 0.56±0.57, 1.73±1.07 and 3.71±0.76 ng/ml respectively in HIE Stage I, II and III cases, thereby showing a signicant incremental trend with increasing HIE stage. Ca Conclusion- rdiac Troponin-I not only showed a signicant correlation with increasing HIE and it was highly useful in prediction of higher stages of HIE and NICU mortality. The ndings of the study show a high potential of cardiac Troponin-I as a marker of HIE severity and outcome in birth asphyxiated neonates.
... After a hypoxic-ischemic attack (i.e., impaired cerebral blood flow and oxygen delivery to the brain), the pathologic events of HIE involve the generation of OS, with the release of oxygen and nitrogen species, calcium overloading, ROS generation, ionic imbalance, inflammation, apoptosis, autophagy, and necrosis [24,25]. ...
During pregnancy, reactive oxygen species (ROS) serve as crucial signaling molecules for fetoplacental circulatory physiology. Oxidative stress is thought to sustain the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). A retrospective study was performed on the brains and placentas of fetuses and newborns between 36–42 weeks of gestation (Group_1: Fetal intrauterine deaths, Group_2: Intrapartum deaths, Group_3: Post-partum deaths, Control group sudden neonatal death); all groups were further divided into two subgroups (Subgroup_B [brain] and Subgroup_P [placenta]), and the study was conducted through the immunohistochemical investigations of markers of oxidative stress (NOX2, 8-OHdG, NT, iNOS), IL-6, and only on the brain samples, AQP4. The results for the brain samples suggest that NOX2, 8-OHdG, NT, iNOS, and IL-6 were statistically significantly expressed above the controls. iNOS was more expressed in the fetal intrauterine death (Group_1) and less expressed in post-partum death (Group_3), while in intrapartum death (Group_2), the immunoreactivity was very low. IL-6 showed the highest expression in the brain cortex of the fetal intrauterine death (Group_1), while intrapartum death (Group_2) and post-partum death (Group_3) showed weak immunoreactivity. Post-partum death (Group_3) placentas showed the highest immunoreactivity to NOX2, which was almost double that of the fetal intrauterine death (Group_1) and intrapartum death (Group_2) placentas. Placental tissues of fetal intrauterine death (Group_1) and intrapartum death (Group_2) showed higher expression of iNOS than post-partum death (Group_3), while the IL-6 expression was higher in the fetal intrauterine death (Group_1) than the post-partum death (Group_3). The AQP4 was discarded as a possible marker because the immunohistochemical reaction in the three groups of cases and the control group was negative. The goal of this study, from the point of view of forensic pathology, is to provide scientific evidence in cases of medical liability in the Obstetric field to support the clinical data of the timing of HIE.
... 38,39 Clinical care has been shown to have neuroprotective effects in HIE. 40 In turn, the newborns in the current sample with severe HIE who had larger brain volumes within the HIE group may have been exposed to additional neuroprotective agents as part of clinical care that were not captured by our analyses. An additional consideration is the babies with severe HIE were a heterogeneous group and the resulting encephalopathy may have resulted from antenatal or postnatal events that were not captured in our analyses that impacted neuronal and/glial processes, which resulted in larger volumes. ...
Background:
Despite treatment with therapeutic hypothermia, hypoxic-ischemic encephalopathy (HIE) is associated with adverse developmental outcomes, suggesting the involvement of subcortical structures including the thalamus and basal ganglia, which may be vulnerable to perinatal asphyxia, particularly during the acute period. The aims were: (1) to examine subcortical macrostructure in neonates with HIE compared to age- and sex-matched healthy neonates within the first week of life; (2) to determine whether subcortical brain volumes are associated with HIE severity.
Methods:
Neonates (n = 56; HIE: n = 28; Healthy newborns from the Developing Human Connectome Project: n = 28) were scanned with MRI within the first week of life. Subcortical volumes were automatically extracted from T1-weighted images. General linear models assessed between-group differences in subcortical volumes, adjusting for sex, gestational age, postmenstrual age, and total cerebral volumes. Within-group analyses evaluated the association between subcortical volumes and HIE severity.
Results:
Neonates with HIE had smaller bilateral thalamic, basal ganglia and right hippocampal and cerebellar volumes compared to controls (all, p < 0.02). Within the HIE group, mild HIE severity was associated with smaller volumes of the left and right basal ganglia (both, p < 0.007) and the left hippocampus and thalamus (both, p < 0.04).
Conclusions:
Findings suggest that, despite advances in neonatal care, HIE is associated with significant alterations in subcortical brain macrostructure.
Impact:
Compared to their healthy counterparts, infants with HIE demonstrate significant alterations in subcortical brain macrostructure on MRI acquired as early as 4 days after birth. Smaller subcortical volumes impacting sensory and motor regions, including the thalamus, basal ganglia, and cerebellum, were seen in infants with HIE. Mild and moderate HIE were associated with smaller subcortical volumes.
Background
Vitamin D has a role in minimizing the extent of neuronal cell injury and death in neonatal hypoxic–ischemic encephalopathy (HIE).
Aim
To assess the serum level of vitamin D in full-term babies with HIE.
Patients and methods
This case–control study was conducted on 40 full-term neonates. Cases were grouped into two groups: group A: 30 full-term neonates diagnosed as HIE; clinical diagnosis was based on Sarnat staging. Group B: 10 healthy full-term neonates. Patients in group A were further subdivided into three equal groups: group A1: grade I HIE, group A2: grade II HIE, and group A3: grade III HIE.
Results
The following investigations were done for groups A and B: Apgar score after 1 and 5 min, convulsions, metabolic acidosis need for respiratory support, blood urea, serum creatinine, C-reactive protein level, serum calcium levels, and 25(OH) vitamin D measurements at 12 and 72 h postnatal. Apgar score, pH, total and ionized calcium, and 25(OH)-D were significantly reduced in HIE (specially grade III), while blood urea, serum creatinine, and C-reactive protein were significantly higher in HIE neonates (grade III).
Conclusion
We could assume that the more severe the grade of HIE, the worse are the laboratory findings.
During a neonate’s stay in the neonatal intensive care unit (NICU), they will undergo many painful, but necessary, procedures to deliver treatment and to monitor physiological status. Many of these methods will involve skin breaks by a needle. While pharmacological analgesics are available for larger procedures like surgeries and intubation, the volume of painful procedures neonates must endure makes the use of pharmacological analgesics impractical for every painful procedure. Due to their immature nervous system, preterm neonates have limited ability to modulate pain. Recent studies have demonstrated that repeated pain endured during the neonatal period is associated with long-term neurological deficits. Over the past decades, studies have begun to quantify the effectiveness of non-pharmacological comfort tools (nonnutritive sucking, swaddling, oral sucrose, ShotBlocker, etc.) in reducing neonatal pain during needles sticks
Hypoxic-ischaemic encephalopathy (HIE) arises from diminished blood flow and oxygen to the neonatal brain during labor, leading to infant mortality or severe brain damage, with a global incidence of 1.5 per 1000 live births. Glucagon-like Peptide 1 Receptor (GLP1-R) agonists, used in type 2 diabetes treatment, exhibit neuroprotective effects in various brain injury models, including HIE. In this study, we observed enhanced neurological outcomes in post-natal day 10 mice with surgically induced hypoxic-ischaemic (HI) brain injury after immediate systemic administration of exendin-4 or semaglutide. Short- and long-term assessments revealed improved neuropathology, survival rates, and locomotor function. We explored the mechanisms by which GLP1-R agonists trigger neuroprotection and reduce inflammation following oxygen-glucose deprivation and HI in neonatal mice, highlighting the upregulation of the PI3/AKT signalling pathway and increased cAMP levels. These findings shed light on the neuroprotective and anti-inflammatory effects of GLP1-R agonists in HIE, potentially extending to other neurological conditions, supporting their potential clinical use in treating infants with HIE.
Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic–ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.
Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed.
Background Neonatal hypoxic-ischemic brain injury (HIBI) results from disruptions to blood supply and oxygen in the perinatal brain. The goal of this study was to measure brain sterol metabolites and plasma oxysterols after injury in a neonatal HIBI mouse model to assess for potential therapeutic targets in the brain biochemistry as well as potential circulating diagnostic biomarkers.
Methods Postnatal day 9 CD1-IGS mouse pups were randomized to HIBI induced by carotid artery ligation followed by 30 minutes at 8% oxygen or to sham surgery and normoxia. Brain tissue was collected for sterol analysis by liquid chromatography with tandem mass spectrometry (LC–MS/MS). Plasma was collected for oxysterol analysis by LC–MS/MS.
Results There were minimal changes in brain sterol concentrations in the first 72 hours after HIBI. In severely injured brains, there was a significant increase in desmosterol, 7-DHC, 8-DHC, and cholesterol 24 hours after injury in the ipsilateral tissue. Lanosterol, 24-dehydrolathosterol, and 14-dehydrozymostenol decreased in plasma 24 hours after injury. Severe neonatal HIBI was associated with increased cholesterol and sterol precursors in the cortex at 24 hours after injury.
Conclusions Differences in plasma oxysterols were seen at 24 hours but were not present at 30 minutes after injury, suggesting that these sterol intermediates would be of little value as early diagnostic biomarkers.
Hypoxic-ischemic encephalopathy (HIE) is a severe birth complication affecting neonates. Around 40–60% of affected neonates die by two years of age or have severe disabilities and neurodevelopmental delays. The early assessments of brain injury using traditional clinical and biochemical indicators do not always align with its severity and recovery. This delays identifying neonates who may benefit from adjuvant therapeutic strategies and monitoring therapy response. Our aim was to identify specific proteins using proteomic approach to predict the severity of neonatal asphyxia so that its outcome can also be prevented. To achieve this goal a case–control study was conducted on 38 neonates, and serum and urine samples were collected within 24 h of life. Clinical findings, biochemical parameters, and outcomes of the neonates were recorded. A tandem mass spectrometry-based quantitative proteomics approach was used to identify proteins in the serum and urine of HIE neonates. Bioinformatics analyses were performed to assess the potential features and competence of the identified differentially expressed proteins. This resulted in identification of 51 differentially expressed proteins which were found common to both serum and urine proteomic data. Some of the promising biomarkers found were APOD, ORM1, SOD1, and FABP1. These proteins were associated with the pathways like Amyloid fiber formation, diseases of programmed cell death, detoxification of reactive oxygen species, and neurodegenerative diseases. This study will pave the way for identifying the biomarkers (proteins) that can screen neonates for brain injury and monitor the disease progression, which may reduce mortality and neurodevelopmental impairment.
Introduction:
Perinatal asphyxia (PA) still causes significant morbidity and mortality. Therapeutic hypothermia (TH) is the only effective therapy for neonates with moderate to severe hypoxic-ischemic encephalopathy after PA. These neonates need additional pharmacotherapy, and both PA and TH may impact physiology and, consequently, pharmacokinetics (PK) and pharmacodynamics (PD).
Areas covered:
This review provides an overview of the available knowledge in PubMed (until November 2022) on the pathophysiology of neonates with PA/TH. In vivo pig models for this setting enable distinguishing the effect of PA versus TH on PK and translating this effect to human neonates. Available asphyxia pig models and methodological considerations are described. A summary of human neonatal PK of supportive pharmacotherapy to improve neurodevelopmental outcomes is provided.
Expert opinion:
To support drug development for this population, knowledge from clinical observations (PK data, real-world data on physiology), preclinical (in vitro and in vivo (minipig)) data, and molecular and cellular biology insights can be integrated into a predictive physiologically-based PK (PBPK) framework, as illustrated by the I-PREDICT project (Innovative physiology-based pharmacokinetic model to predict drug exposure in neonates undergoing cooling therapy). Current knowledge, challenges, and expert opinion on the future directions of this research topic are provided.
Neonatal-hypoxic ischemic encephalopathy (HIE) is the leading cause of acquired neonatal brain injury with the risk of developing serious neurologic sequelae and death. An accurate and robust prediction of short- and long-term outcomes may provide clinicians and families with fundamental evidence for their decision-making, the design of treatment strategies, and the discussion of developmental intervention plans after discharge. Diffusion tensor imaging (DTI) is one of the most powerful neuroimaging tools with which to predict the prognosis of neonatal HIE by providing microscopic features that cannot be assessed by conventional MRI. DTI provides various scalar measures that represent the properties of the tissue, such as fractional anisotropy (FA) and mean diffusivity (MD). Since the characteristics of the diffusion of water molecules represented by these measures are affected by the microscopic cellular and extracellular environment, such as the orientation of structural components and cell density, they are often used to study the normal developmental trajectory of the brain and as indicators of various tissue damage, including HIE-related pathologies, such as cytotoxic edema, vascular edema, inflammation, cell death, and Wallerian degeneration. Previous studies have demonstrated widespread alteration in DTI measurements in severe cases of HIE and more localized changes in neonates with mild-to-moderate HIE. In an attempt to establish cutoff values to predict the occurrence of neurological sequelae, MD and FA measured in the corpus callosum (CC), thalamus, basal ganglia, corticospinal tract (CST), and frontal white matter have proven to have an excellent ability to predict severe neurological outcomes. In addition, a recent study has suggested that a data-driven, unbiased approach using machine-learning techniques on features obtained from whole-brain image quantification may accurately predict the prognosis of HIE, including for mild-to-moderate cases. Further efforts are needed to overcome current challenges, such as MRI infrastructure, diffusion modeling methods, and data harmonization for clinical application. In addition, external validation of predictive models is essential for clinical application of DTI to prognostication.
To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE).
We enrolled infants in the intensive care nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to 4 doses adjusted for volume and red blood cell content, 1-5 × 10(7) cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post-infusion vital signs. As exploratory analyses, we compared cell recipients' hospital outcomes (mortality, oral feeds at discharge) and 1-year survival with Bayley Scales of Infant and Toddler Development, 3rd edition scores ≥85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells.
Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 mL. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1-year outcomes survived with scores >85.
Collection, preparation, and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed.
Current available therapies for neonatal hypoxia/ischemia (H/I) brain injury are rather limited. Here, we investigated the effect of omega-3 polyunsaturated fatty acids on brain damage and long-term neurological function after H/I in neonates.
Female rats were treated with or without an omega-3 polyunsaturated fatty acids-enriched diet from the second day of pregnancy until 14 days after parturition. Seven-day-old neonates were subjected to H/I and euthanized 5 weeks later for evaluation of tissue loss. Neurological impairment was assessed progressively for 5 weeks after H/I by grid walking, foot fault, and Morris water maze. Activation of microglia and production of inflammatory mediators were examined up to 7 days after H/I.
Omega-3 polyunsaturated fatty acid supplementation significantly reduced brain damage and improved long-term neurological outcomes up to 5 weeks after neonatal H/I injury. Omega-3 polyunsaturated fatty acids exerted an anti-inflammatory effect in microglia both in an in vivo model of H/I and in in vitro microglial cultures subjected to inflammatory stimuli by inhibiting NF-κB activation and subsequent release of inflammatory mediators.
Our results suggest that omega-3 polyunsaturated fatty acids confer potent neuroprotection against neonatal H/I brain injury through, at least partially, suppressing a microglial-mediated inflammatory response.
Mesenchymal stem cell (MSC) transplantation is a promising therapy to regenerate the brain after an ischemic event. We investigated the possibility to use the nasal route as a noninvasive method to repair the neonatal damaged brain. Nine-day-old mice underwent cerebral hypoxia-ischemia (HI), and MSCs were transplanted intranasally 10 d after HI. At 28 d after HI, MSCs were still present in the affected hemisphere but had not differentiated into cerebral cell types. Intranasal MSC treatment significantly improved sensorimotor function in the cylinder rearing test at 21 and 28 d after HI. Furthermore, intranasal MSC treatment decreased gray and white matter area loss when determined 28 d after HI by 34 and 37%, respectively. MSC cultured in vitro with brain extracts obtained 10 d after HI, responded to the ischemic brain by up-regulation of several growth factors, including fibroblast growth factor 2 and nerve growth factor in comparison with brain extracts of sham-operated controls. In conclusion, MSC can reliably be delivered to the brain via the nasal route to induce functional recovery and a reduction in brain lesion size. We propose that MSC function by stimulating endogenous cerebral repair by adapting their secretion profile to the ischemic brain leading to up-regulation of repair promoting factors.
Moderate to severe hypoxic-ischemic injury in newborn infants, manifested as encephalopathy immediately or within hours after birth, is associated with a high risk of either death or a lifetime with disability. In recent multicenter clinical trials, hypothermia initiated within the first 6 postnatal hours has emerged as a therapy that reduces the risk of death or impairment among infants with hypoxic-ischemic encephalopathy. Prior to hypothermia, no therapies directly targeting neonatal encephalopathy secondary to hypoxic-ischemic injury had convincing evidence of efficacy. Hypothermia therapy is now becoming increasingly available at tertiary centers. Despite the deserved enthusiasm for hypothermia, obstetric and neonatology caregivers, as well as society at large, must be reminded that in the clinical trials more than 40% of cooled infants died or survived with impairment. Although hypothermia is an evidence-based therapy, additional discoveries are needed to further improve outcome after HIE. In this article, we briefly present the epidemiology of neonatal encephalopathy due to hypoxic-ischemic injury, describe the rationale for the use of hypothermia therapy for hypoxic-ischemic encephalopathy, and present results of the clinical trials that have demonstrated the efficacy of hypothermia. We also present findings noted during and after these trials that will guide care and direct research for this devastating problem.
The goal was to examine biochemical, neurophysiologic, anatomic, and clinical changes associated with erythropoietin administration to neonates with hypoxic-ischemic encephalopathy (HIE).
We conducted a prospective case-control study with 45 neonates in 3 groups, a normal healthy group (N = 15), a HIE-erythropoietin group (N = 15; infants with mild/moderate HIE who received human recombinant erythropoietin, 2500 IU/kg, subcutaneously, daily for 5 days), and a HIE-control group (N = 15; did not receive erythropoietin). Serum concentrations of nitric oxide (NO) were measured at enrollment for the normal healthy neonates and at enrollment and after 2 weeks for the 2 HIE groups. The 2 HIE groups underwent electroencephalography at enrollment and at 2 to 3 weeks. Brain MRI was performed at 3 weeks. Neurologic evaluations and Denver Developmental Screening Test II assessments were performed at 6 months.
Compared with normal healthy neonates, the 2 HIE groups had greater blood NO concentrations (P < .001). At enrollment, the 2 HIE groups did not differ in clinical severity, seizure incidence, NO concentrations, or electroencephalographic findings. At 2 weeks of age, electroencephalographic backgrounds improved significantly (P = .01) and NO concentrations decreased (P < .001) in the HIE-erythropoietin group, compared with the HIE-control group; MRI findings did not differ between groups. At 6 months of age, infants in the HIE-erythropoietin group had fewer neurologic (P = .03) and developmental (P = .03) abnormalities.
This study demonstrates the feasibility of early administration of human recombinant erythropoietin to term neonates with HIE, to protect against encephalopathy.
To determine whether moderate hypothermia after hypoxic-ischaemic encephalopathy in neonates improves survival and neurological outcome at 18 months of age.
A meta-analysis was performed using a fixed effect model. Risk ratios, risk difference, and number needed to treat, plus 95% confidence intervals, were measured.
Studies were identified from the Cochrane central register of controlled trials, the Oxford database of perinatal trials, PubMed, previous reviews, and abstracts. Review methods Reports that compared whole body cooling or selective head cooling with normal care in neonates with hypoxic-ischaemic encephalopathy and that included data on death or disability and on specific neurological outcomes of interest to patients and clinicians were selected. Results We found three trials, encompassing 767 infants, that included information on death and major neurodevelopmental disability after at least 18 months' follow-up. We also identified seven other trials with mortality information but no appropriate neurodevelopmental data. Therapeutic hypothermia significantly reduced the combined rate of death and severe disability in the three trials with 18 month outcomes (risk ratio 0.81, 95% confidence interval 0.71 to 0.93, P=0.002; risk difference -0.11, 95% CI -0.18 to -0.04), with a number needed to treat of nine (95% CI 5 to 25). Hypothermia increased survival with normal neurological function (risk ratio 1.53, 95% CI 1.22 to 1.93, P<0.001; risk difference 0.12, 95% CI 0.06 to 0.18), with a number needed to treat of eight (95% CI 5 to 17), and in survivors reduced the rates of severe disability (P=0.006), cerebral palsy (P=0.004), and mental and the psychomotor developmental index of less than 70 (P=0.01 and P=0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected. Mortality was significantly reduced when we assessed all 10 trials (1320 infants; relative risk 0.78, 95% CI 0.66 to 0.93, P=0.005; risk difference -0.07, 95% CI -0.12 to -0.02), with a number needed to treat of 14 (95% CI 8 to 47).
In infants with hypoxic-ischaemic encephalopathy, moderate hypothermia is associated with a consistent reduction in death and neurological impairment at 18 months.
Human umbilical cord blood mononuclear cells (HUCB) have been shown to have a therapeutic role in different models of central nervous system (CNS) damage, including stroke. We evaluated the possible therapeutic potential of HUCB in P7 rats submitted to the Rice-Vannucci model of neonatal hypoxic-ischemic (HI) brain damage. Our results demonstrated that intraperitoneal transplantation of HUCB, 3 h after the HI insult, resulted in better performance in two developmental sensorimotor reflexes, in the first week after the injury. We also showed a neuroprotective effect in the striatum, and a decrease in the number of activated microglial cells in the cerebral cortex of treated animals. We suggest that HUCB transplantation might rescue striatal neurons from cell death after a neonatal HI injury resulting in better functional recovery.
Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport.
Hypothermia (HT) improves outcome after neonatal hypoxia-ischemia. Combination therapy may extend neuroprotection. The noble anesthetic gas xenon (Xe) has an excellent safety profile. We have shown earlier that 3 h of 50% Xe plus HT (32 degrees C) additively gives more protection (72%) than either alone (HT=31.1%, Xe=10.2%). Factors limiting clinical use include high-cost and specialist administration requirements. Thus, combinations of 1 h of 50% Xe were administered concurrently for either the first (1 h(Immediate)Xe) or last (1 h(Delayed)Xe) of 3 h of posthypoxic-ischemic HT as compared with 3 h of 50%Xe/HT to investigate how brief Xe exposure with a delay would affect efficacy. An established neonatal rat hypoxia-ischemia model was used. Serial functional neurologic testing into adulthood was performed, followed by neuropathological examination. Xenon with HT was more effective with longer Xe duration (3 h versus 1 h) (P=0.015). However, 1 h Xe/3 h HT resulted in better neuroprotection than 3 h HT alone (P=0.03), this significant effect was also present with 1 h Xe after a 2-h delay. One (immediate or with a delay) or 3 h Xe also significantly improved motor function (P=0.024). Females had significantly better motor scores than males, but no sex-dependent difference in pathology results. The neuroprotection of short, delayed Xe treatment would allow transport to specialist facilities to receive Xe.
Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial.
Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age.
A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups.
Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories.
Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.
Proton magnetic resonance spectroscopy (1H MRS) was performed within 18 h of birth (median 13, range 4-18 h) on 16 term infants with clinical features of birth asphyxia. Ten infants with no evidence of birth asphyxia were studied as controls at 5-18 (median 8) h after birth. To detect delayed impairments in cerebral energy metabolism, 15 infants suspected of asphyxia underwent 31P MRS at 33-106 (median 62) h of age. Choline, creatine, and N-acetylaspartate (NAA) were detected in spectra located to the basal ganglia in all infants. Lactate was detected in 15 of the 16 infants suspected of asphyxia, but in only 4 of the 10 controls (p < 0.05, chi 2). Glutamine and glutamate (Glx) was detected in 11 infants suspected of asphyxia and in three controls, but this difference was not significant at the 5% level. The spectra revealed no other significant differences between asphyxiated infants and controls. In the asphyxiated infants, there was a negative correlation between the ratio of lactate to creatine in the first 18 h of life and phosphocreatine/inorganic phosphate (PCr/ P(i)) at 33-106 h (p < 0.001). Five severely asphyxiated infants had PCr/P(i) < 0.75 (median 0.53, range 0.14-0.65), indicating a poor neurodevelopmental prognosis, and a further infant died before PCr/Pi could be measured. Ten infants had PCr/P(i) > 0.75 (1.03, 0.76-1.49). Median lactate/creatine was 1.47 (range 0.67-3.81) in the six severely affected subjects, 0.38 (0-1.51) in the latter group, and 0 (0-0.6) in controls (p < 0.0005, Kruskall-Wallis). These results suggest that, after birth asphyxia, cerebral energy metabolism is abnormal during the period when 31P MRS characteristically gives normal results. 1H MRS might be of value in predicting which infants are likely to suffer a decline in cerebral high energy phosphate concentrations and subsequent neurodevelopmental impairment.
Hypothermia has been proposed as a neuroprotective strategy. However, short-term cooling after hypoxia-ischemia is effective only if started immediately during resuscitation. The aim of this study was to determine whether prolonged head cooling, delayed into the late postinsult period, improves outcome from severe ischemia. Unanesthetized near term fetal sheep were subject to 30 min of cerebral ischemia. 90 min later they were randomized to either cooling (n = 9) or sham cooling (n = 7) for 72 h. Intrauterine cooling was induced by a coil around the fetal head, leading initially to a fall in extradural temperature of 5-10 degrees C, and a fall in esophageal temperature of 1.5-3 degrees C. Cooling was associated with mild transient systemic metabolic effects, but not with hypotension or altered fetal heart rate. Cerebral cooling reduced secondary cortical cytotoxic edema (P < 0.001). After 5 d of recovery there was greater residual electroencephalogram activity (-5.2+/-1.6 vs. -15.5+/-1.5 dB, P < 0.001) and a dramatic reduction in the extent of cortical infarction and neuronal loss in all regions assessed (e.g., 40 vs. 99% in the parasagittal cortex, P < 0.001). Selective head cooling, maintained throughout the secondary phase of injury, is noninvasive and safe and shows potential for improving neonatal outcome after perinatal asphyxia.
Neonatal encephalopathy (NE) is the clinical manifestation of disordered neonatal brain function. Lack of universal agreed definitions of NE and the sub-group with hypoxic-ischaemia (HIE) makes the estimation of incidence and the identification of risk factors problematic. NE incidence is estimated as 3.0 per 1000 live births (95%CI 2.7 to 3.3) and for HIE is 1.5 (95%CI 1.3 to 1.7). The risk factors for NE vary between developed and developing countries with growth restriction the strongest in the former and twin pregnancy in the latter. Potentially modifiable risk factors include maternal thyroid disease, receipt of antenatal care, infection and aspects of the management of labour and delivery, although indications for some interventions were not reported and may represent a response to fetal compromise rather than the cause. It is estimated that 30% of cases of NE in developed populations and 60% in developing populations have some evidence of intrapartum hypoxic-ischaemia.
Deferoxamine (DFO) and erythropoietin (EPO) have each been shown to provide neuroprotection in neonatal rodent models of brain injury. In view of the described anti-oxidative actions of DFO and the anti-apoptotic and anti-inflammatory effects of EPO, we hypothesized that the combination of DFO and EPO would increase neuroprotection after neonatal hypoxic-ischemic brain injury as compared to single DFO or EPO treatment. At postnatal day 7 rats underwent right common carotid artery occlusion followed by a 90-min exposure to 8% oxygen. Rats were treated intraperitoneally with DFO (200mg/kg), recombinant human EPO (1 kU/kg), a combination of DFO-EPO or vehicle at 0, 24 and 48 h after hypoxia-ischemia (HI) and were sacrificed at 72 h. DFO-EPO administration reduced the number of cleaved caspase 3-positive cells in the ipsilateral cerebral cortex. Early neuronal damage was assessed by staining for microtubuli-associated protein (MAP)-2. In our model 63+/-9% loss of ipsilateral MAP-2 was observed after HI, indicating extensive brain injury. DFO, EPO or DFO-EPO treatment did not improve neuronal integrity as defined by MAP-2. Cerebral white matter tracts were stained for myelin basic protein (MBP), a constituent of myelin. Hypoxia-ischemia strongly reduced MBP staining which suggests white matter damage. However, DFO, EPO and DFO-EPO treatment had no effect on the loss of MBP staining. Finally, HI-induced loss of striatal tyrosine hydroxylase staining was not attenuated by DFO, EPO or DFO-EPO. Although DFO-EPO treatment reduced the number of cleaved caspase 3(+) cells, treatment with DFO, EPO, or with the combination of DFO and EPO did not protect against gray or white matter damage in the experimental setting applied.
Hypoxic ischemia is a common cause of damage to the fetal and neonatal brain. Although systemic and cerebrovascular physiologic factors play an important role in the initial phases of hypoxic-ischemic injuries, the intrinsic vulnerability of specific cell types and systems in the developing brain may be more important in determining the final pattern of damage and functional disability. Excitotoxicity, a term applied to the death of neurons and certain other cells caused by overstimulation of excitatory, mainly glutamate, neurotransmitter receptors, plays a critical role in these processes. Selected neuronal circuits as well as certain populations of glia such as immature periventricular oligodendroglia may die from excitotoxicity triggered by hypoxic ischemia. These patterns of neuropathologic vulnerability are associated with clinical syndromes of neurologic disability such as the extrapyramidal and spastic diplegia forms of cerebral palsy. The cascade of biochemical and histopathologic events triggered by hypoxic ischemia can extend for days to weeks after the insult is triggered, creating the potential for therapeutic interventions.Abbreviations: Ca2+, calcium; FD-glucose, fluorodeoxyglucose; HIE, hypoxic-ischemic encephalopathy; MR, magnetic resonance; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NMDA, N-methyl-d-aspartate a subtype of glutamate receptor; PET, positron emission tomography
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Using immunohistochemistry, expression of erythropoietin (EPO), a hypoxia-inducible neuroprotective factor, and its receptor (EPOR) were investigated in human brain tissue after ischemia/hypoxia. Autopsy brains of neuropathologically normal subjects were compared to those with ischemic infarcts or hypoxic damage. In normal brain, weak EPO/EPOR immunoreactivity was mainly neuronal. In fresh infarcts, EPO immunoreactivity appeared in vascular endothelium, EPOR in microvessels and neuronal fibers. In older infarcts reactive astrocytes exhibited EPO/EPOR immunoreactivity. Acute hypoxic brain damage was associated with vascular EPO expression, older hypoxic damage with EPO/EPOR immunoreactivity in reactive astrocytes. The pronounced up-regulation of EPO/EPOR in human ischemic/hypoxic brains underlines their role as an endogenous neuroprotective system and suggests a novel therapeutic potential in cerebrovascular disease for EPO, a clinically well-characterized and safe compound.
Hypoxic ischemic encephalopathy (HIE) describes neonatal encephalopathy that is caused by intrapartum asphyxia and it can result in the long term sequelae of cerebral palsy which is a major cause of disability. The incidence of cerebral palsy has not changed over the last few decades and the challenge to obstetricians remains how best to recognise those babies at risk of this intrapartum insult both before and during labour. Many associations and risk factors are unavoidable or unrecognisable, and others are fairly common and associated with poor predictive value. Intrapartum fetal heart monitoring remains the main focus of attention but how this is best achieved is still the subject of research. Computerised decision support systems built into fetal heart rate monitoring and non-invasive fetal ECG signal pick-up are currently being explored.
Hypoxic ischaemic encephalopathy continues to be a significant cause of death and disability worldwide. In the last 1-2 years, therapeutic hypothermia has entered clinical practice in industrialized countries and neuroprotection of the newborn has become a reality. The benefits and safety of cooling under intensive care settings have been shown consistently in trials; therapeutic hypothermia reduces death and neurological impairment at 18 months with a number needed to treat of approximately nine. Unfortunately, around half the infants who receive therapeutic hypothermia still have abnormal outcomes. Recent experimental data suggest that the addition of another agent to cooling may enhance overall protection either additively or synergistically. This review discusses agents such as inhaled xenon, N-acetylcysteine, melatonin, erythropoietin and anticonvulsants. The role of biomarkers to speed up clinical translation is discussed, in particular, the use of the cerebral magnetic resonance spectroscopy lactate/N-acetyl aspartate peak area ratios to provide early prognostic information. Finally, potential future therapies such as regeneration/repair and postconditioning are discussed.
There is now a strong evidence base supporting therapeutic hypothermia for infants with moderate or severe neonatal hypoxic ischaemic encephalopathy. Experimental and clinical data indicate that induced hypothermia reduces cerebral hypoxic ischaemic injury and randomized clinical trials in newborns with hypoxic ischaemic encephalopathy confirm improved neurological outcomes and survival at 18 months of age with therapeutic hypothermia. Studies are on-going to confirm whether these benefits are maintained in later childhood. Efforts are now focused on optimal implementation of therapeutic hypothermia in clinical practice: training in the assessment of severity of encephalopathy; initiation and maintenance of hypothermia before admission to a cooling facility; care of the infant during cooling; and appropriate investigation and follow-up are crucial for optimizing neurological outcomes. The establishment of registries of infants with hypoxic ischaemic encephalopathy and audit are important for guiding clinical practice.
To investigate whether topiramate associated with mild or deep hypothermia in asphyxiated term infants is safe in relation to the short-term outcome.
We report on 27 consecutive asphyxiated newborns who were treated with whole body hypothermia and 27 additional consecutive newborns with hypothermia who were co-treated with oral topiramate, once a day for 3 consecutive days, at 2 different doses.
Newborns were divided in 6 groups according to the depth of hypothermia and the association with higher or lower topiramate dosage. A statistical comparison of the groups identified some differences in biochemical and hemodynamic variables, but no adverse effects attributable to topiramate were detected. There were no statistically significant differences in the groups in short-term outcomes, survival rate at discharge, or incidence of pathologic brain magnetic resonance imaging.
Although the number of newborns in this study was limited, the short-term outcome and the safety data appear to support the evaluation of topiramate in clinical trials to explore its possible additive neuroprotective action.
Low-dose lipopolysaccharide (LPS) preconditioning provides neonatal rats long-term neuroprotection against hypoxic ischemia (HI). Upregulating endothelial nitric oxide synthase (eNOS) protects against cerebral ischemia; however, whether eNOS is required for LPS preconditioning-induced protection in neonatal rats is unknown. We hypothesized that Akt activation, which upregulates eNOS in neurons and endothelial cells, is required for LPS preconditioning-induced tolerance against HI in the neonatal brain.
Six-day-old rat pups were intraperitoneally injected with LPS (0.05 mg/kg) or normal saline 24 hours before HI. Immunoblotting and immunohistochemistry were used to determine the phospho-Akt (pAkt Ser473), phospho-eNOS (peNOS Ser1177), and eNOS levels and immunofluorescence to determine the cellular distribution of eNOS and pAkt Ser473. Pharmacological and genetic approaches were used to regulate Akt and eNOS, and the weight loss of cerebral hemispheres on postnatal Day 21 was used to assess outcomes.
eNOS, peNOS (Ser1177), and pAkt (Ser473) levels were significantly higher in LPS- than in normal saline-treated rats 24 hours postinjection. LPS-induced eNOS was expressed primarily in neurons and vascular endothelial cells. N-omega(omega)-nitro-L-arginine and antisense oligodeoxynucleotide treatment significantly reduced eNOS expression in neurons and endothelial cells and inhibited LPS-induced protection against HI in rat pups. L-arginine and adenovirus eNOS transfection upregulated eNOS and protected the rat pups against HI. Wortmannin treatment before LPS preconditioning significantly reduced eNOS expression in neurons and endothelial cells, which inhibited LPS-induced protection against HI.
Akt-mediated eNOS upregulation in neurons and vascular endothelial cells is required for LPS-induced tolerance against HI in the neonatal rat brain.
Hypoxic-ischemic encephalopathy due to neonatal asphyxia is one of the most important causes of delayed neurological development. Prolonged neuronal apoptosis plays an important role in the processes contributing to neuronal degeneration. Docosahexaenoic acid (DHA), a major component of brain membrane phospholipids, prevents neuronal cell apoptosis and plays an important role as an anti-oxidant agent. We investigated the neuroprotective and anti-oxidant effects of maternal DHA supplementation during pregnancy in a model of neonatal hypoxic-ischemic encephalopathy. Pregnant rats were randomly assigned to two experimental groups: a control group or a DHA-enriched diet group. Hypoxic-ischemic encephalopathy was produced by left common carotid artery occlusion and exposure to 8% oxygen for 1.5 h. TUNEL assay, immunohistochemistry for caspase-3 and 8-hydroxy-deoxyguanosine (8-OHdG), and Western blot for caspase-3 were performed at postnatal days 8, 10 and 14. Fatty acid composition of brain was estimated on postnatal day 7. Maternal diet clearly influenced brain fatty acid composition in pups. Numbers of apoptotic neuronal cells and 8-OHdG immunoreactivity were significantly decreased in the DHA-enriched group. Our findings indicate that maternal DHA-enriched diet during pregnancy provides neuroprotection by inhibiting oxidative stress and apoptotic neuronal death. Dietary supplementation of DHA during pregnancy may thus be beneficial in preventing neonatal brain injury.
Hypothermia is a potential neuroprotective intervention to treat neonatal post-asphyxial (hypoxic-ischemic) encephalopathy (HIE). In this meta-analysis of 13 clinical trials published to date, therapeutic hypothermia was associated with a highly reproducible reduction in the risk of the combined outcome of mortality or moderate-to-severe neurodevelopmental disability in childhood. This improvement was internally consistent, as shown by significant reductions in the individual risk for death, moderate-to-severe neurodevelopmental disability, severe cerebral palsy, cognitive delay, and psychomotor delay. Patients in the hypothermia group had higher incidences of arrhythmia and thrombocytopenia; however, these were not clinically important. This analysis supports the use of hypothermia in reducing the risk of the mortality or moderate-to-severe neurodevelopmental disability in infants with moderate HIE.
The general anesthetic gas xenon is neuroprotective and is undergoing clinical trials as a treatment for ischemic brain injury. A small number of molecular targets for xenon have been identified, the N-methyl-D-aspartate (NMDA) receptor, the two-pore-domain potassium channel TREK-1, and the adenosine triphosphate-sensitive potassium channel (KATP). However, which of these targets are relevant to acute xenon neuroprotection is not known. Xenon inhibits NMDA receptors by competing with glycine at the glycine-binding site. We test the hypothesis that inhibition of the NMDA receptor at the glycine site underlies xenon neuroprotection against hypoxia-ischemia.
We use an in vitro model of hypoxia-ischemia to investigate the mechanism of xenon neuroprotection. Organotypic hippocampal brain slices from mice are subjected to oxygen-glucose deprivation, and injury is quantified by propidium iodide fluorescence.
We show that 50% atm xenon is neuroprotective against hypoxia-ischemia when applied immediately after injury or after a delay of 3 h after injury. To validate our method, we show that neuroprotection by gavestinel is abolished when glycine is added, confirming that NMDA receptor glycine site antagonism underlies gavestinel neuroprotection. We then show that adding glycine abolishes the neuroprotective effect of xenon, consistent with competitive inhibition at the NMDA receptor glycine site mediating xenon neuroprotection.
We show that xenon neuroprotection against hypoxia- ischemia can be reversed by increasing the glycine concentration. This is consistent with competitive inhibition by xenon at the NMDA receptor glycine site, playing a significant role in xenon neuroprotection. This finding may have important implications for xenon's clinical use as an anesthetic and neuroprotectant.
Seizures are associated with adverse outcome in infants with hypoxic-ischemic encephalopathy. We hypothesized that early administration of the anticonvulsant phenobarbital after cerebral hypoxia ischemia could enhance the neuroprotective efficacy of delayed-onset hypothermia. We tested this hypothesis in a neonatal rodent model. Seven-d-old rats (n = 104) underwent right carotid ligation, followed by 90 min 8% O2 exposure; 15 min later, they received injections of phenobarbital (40 mg/kg) or saline. One or 3 h later, all were treated with hypothermia (30 degrees C, 3 h). Function and neuropathology were evaluated after 7 d (early outcomes) or 1 mo (late outcomes). Early outcome assessment demonstrated better sensorimotor performance and less cortical damage in phenobarbital-treated groups; there were no differences between groups in which the hypothermia delay was shortened from 3 to 1 h. Late outcome assessment confirmed sustained benefits of phenobarbital + hypothermia treatment; sensorimotor performance was better (persistent attenuation of contralateral forepaw placing deficits and absence of contralateral forepaw neglect); neuropathology scores were lower (median, phenobarbital 2 and saline 8.5, p < 0.05); and less ipsilateral cerebral hemisphere %Damage (mean +/- SD, 11 +/- 17 versus 28 +/- 22, p < 0.05). These results suggest that early posthypoxia-ischemia administration of phenobarbital may augment the neuroprotective efficacy of therapeutic hypothermia.
Our aim was to document changes in the evaluation and prognosis of term-born infants with neonatal encephalopathy of hypoxic-ischemic origin, with particular reference to our own experiences and influences, and to summarize the debate on causation and the relative importance of antenatal and perinatal factors. High quality neonatal cranial ultrasound and magnetic resonance imaging and spectroscopy have enabled the accurate early visualization of different patterns of hypoxic-ischemic brain injury and prediction of their associated outcomes. Long-term follow-up shows that cognitive and memory difficulties may follow even in children without motor deficits. The very early use of electrophysiologic methods has allowed broad prognostic categorization of infants when this is not possible from clinical assessment or imaging, providing a rationale for entry into intervention trials, such as therapeutic hypothermia. This work has also shown that most of these infants have evidence of acute hypoxic-ischemic brain injury that explains their symptoms and outcomes.
Hypoxia-ischemia in the perinatal period is an important cause of cerebral palsy and associated disabilities in children. There has been significant research progress in hypoxic-ischemic encephalopathy over the last 2 decades, and many new molecular mechanisms have been identified. Despite all these advances, therapeutic interventions are still limited. In this article the authors discuss several molecular pathways involved in hypoxia-ischemia, and potential therapeutic targets.
To investigate the mechanisms involved in cannabidiol (CBD)-induced neuroprotection in hypoxic-ischemic (HI) immature brain, forebrain slices from newborn mice underwent oxygen and glucose deprivation in the presence of vehicle, or CBD alone or with selective antagonists of cannabinoid CB(1) and CB(2), and adenosine A(1) and A(2) receptors. CBD reduced acute (LDH efflux to the incubation medium) and apoptotic (caspase-9 concentration in tissue) HI brain damage by reducing glutamate and IL-6 concentration, and TNFalpha, COX-2, and iNOS expression. CBD effects were reversed by the CB(2) antagonist AM630 and by the A(2A) antagonist SCH58261. The A(1A) antagonist DPCPX only counteracted the CBD reduction of glutamate release, while the CB(1) antagonist SR141716 did not modify any effect of CBD. In conclusion, CBD induces robust neuroprotection in immature brain, by acting on some of the major mechanisms underlying HI cell death; these effects are mediated by CB(2) and adenosine, mainly A(2A), receptors.
Birth asphyxia is a frequent cause of perinatal morbidity and mortality and treatment options are very limited. Our aim was to determine the effects of treatment with bone marrow-derived mesenchymal stem cells (MSC) after neonatal hypoxic-ischemic brain injury (HI). Nine-day old mice were exposed to cerebral HI and endogenous cell proliferation was determined by BrdU-incorporation. Maximal endogenous cell proliferation, indicative for a trophic milieu, was observed at 3 days after HI. MSC transplantation at this time point decreased neuronal and oligodendrocyte loss when determined 21 days after HI by 42% and 31%, respectively. MSC treatment enhanced BrdU-incorporation in the ischemic hemisphere mainly in cells of recipient origin. The percentage of recently divided neurons and oligodendrocytes in hippocampus and cortex was increased after MSC transplantation. MSC treatment reduced the percentage of cortical and increased the percentage of hippocampal BrdU+-astrocytes. The percentage of BrdU+-microglia decreased after MSC treatment. Motoric behavior in the cylinder rearing test at 10 and 21 days after HI was significantly improved by MSC treatment 3 days after the insult. Moreover, even when treatment was started at 10 days after HI, there was a significant reduction in lesion size and improvement of behavioral outcome. Our data show that MSC treatment after neonatal HI brain damage improved functional outcome, reduced lesion volume, increased differentiation of recently divided cells towards neurons and oligodendrocytes and decreased proliferating inflammatory cells. We propose that MSC transplantation is a powerful treatment to improve behavioral outcome and cerebral lesion volume after neonatal brain damage via stimulation of endogenous repair processes.
Summary:
Background: Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy.
Methods: 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34–35°C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation—ie, severe loss of background amplitude, and seizures—and those with less severe changes.
Findings: In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0·61; 95% CI 0·34–1·09, p=0·1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0·57 (0·32–1·01, p=0·05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1·8; 0·49–6·4, p=0·51), but was beneficial in infants with less severe aEEG changes (n= 172, 0·42; 0·22–0·80, p=0·009).
Interpretation: These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.
The volatile anesthetics desflurane, isoflurane, and sevoflurane have been found to produce neuroprotection in various paradigms. The authors used these agents in a delayed preconditioning model to test the hypothesis that they could provide neuroprotection against neonatal hypoxia-ischemia as assessed by a battery of behavioral tests.
Institutional Animal Care and Use Committee approval was obtained. A total of 140, C57-129T2 F1 hybrid 9-day-old mice were randomized to 3 h of preconditioning with room air (Group Sham and Group HI), 8.4% desflurane in 40% oxygen (Group D), 1.8% isoflurane (Group I), or 3.1% sevoflurane (Group S). Twenty-four hours later, the Group HI, D, I, and S mice had 60 min of hypoxia-ischemia, and Group Sham had 60 min of sham HI. Surviving animals had behavioral testing, including open field activity, acoustic startle, prepulse inhibition, rotorod, novel object recognition, water mazes, and apomorphine challenge. Histologic analysis was also performed.
Mice in Groups D, I, and S performed better than Group HI and similarly to Group Sham on novel object recognition and apomorphine challenge and better than Group HI but not as well as Group Sham on cued maze testing. All mice exposed to hypoxia-ischemia performed worse than Group Sham on the spatially oriented water mazes with no difference among groups. Histologic sections did not show any significant effect of preconditioning on injury scores.
Volatile agent preconditioning partially protects perirhinal cortex and striatal dependent functions against moderate to severe neonatal hypoxia-ischemia.
The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy (HIE), by using a randomized, prospective study design.
A total of 167 term infants with moderate/severe HIE were assigned randomly to receive either erythropoietin (N = 83) or conventional treatment (N = 84). Recombinant human erythropoietin, at either 300 U/kg (N = 52) or 500 U/kg (N = 31), was administered every other day for 2 weeks, starting <48 hours after birth. The primary outcome was death or disability. Neurodevelopmental outcomes were assessed at 18 months of age.
Complete outcome data were available for 153 infants. Nine patients dropped out during treatment, and 5 patients were lost to follow-up monitoring. Death or moderate/severe disability occurred for 35 (43.8%) of 80 infants in the control group and 18 (24.6%) of 73 infants in the erythropoietin group (P = .017) at 18 months. The primary outcomes were not different between the 2 erythropoietin doses. Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE (P = .001) and not those with severe HIE (P = .227). No negative hematopoietic side effects were observed.
Repeated, low-dose, recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE, without apparent side effects.
Asphyxia accounts for 23% of the 4 million annual global neonatal deaths. In developed countries, the incidence of death or severe disability after hypoxic-ischemic (HI) encephalopathy is 1-2/1000 infants born at term. Hypothermia (HT) benefits newborns post-HI and is rapidly entering clinical use. Xenon (Xe), a scarce and expensive anesthetic, combined with HT markedly increases neuroprotection in small animal HI models. The low-Xe uptake of the patient favors the use of closed-circuit breathing system for efficiency and economy. We developed a system for delivering Xe to mechanically ventilated neonates, then investigated its technical and practical feasibility in a previously described neonatal pig model approximating the clinical scenario of global HI injury, prolonged Xe delivery with and without HT as a potential therapy, subsequent neonatal intensive care unit management, and tracheal extubation.
Sixteen newborn pigs underwent a global 45 min HI insult (4%-6% inspired oxygen reducing the electroencephalogram amplitude to <7 microV), then received 16 h 50% inspired Xe during normothermia (39.0 degrees C) or HT (33.5 degrees C). A conventional neonatal ventilator provided breaths of oxygen to a lower chamber compressing a hanging bag within. This bag communicated with the upper closed part of the breathing system containing soda lime, unidirectional valves, Xe/oxygen analyzers, and a tracheal tube connection. At each end-inspiration, this bag emptied fully and a bolus of oxygen, the driving gas, crossed from the lower to upper chamber via an additional valve. This mechanically substituted the gas uptake from the circle during the previous breath cycle (oxygen + small volume of Xe) with an equivalent volume of oxygen creating a slow-rising inspired oxygen concentration. This was offset by manual injection of Xe boluses, infrequently at steady state, due to the low-Xe uptake of the patient.
Total mean Xe usage was 0.18 (0.16-0.21) L/h with no differences between Xe-HT and Xe-NT groups, which had weights of 1767 (1657-1877) g and 1818 (1662-1974) g, respectively (95% CI). HT reduced heart rate in the cooled animals; 180 (165-195) vs 148 (142-155) bpm (P < 0.0001) with no differences in arterial blood pressure, oxygen saturation, arterial carbon dioxide tension, or weaning times between these groups.
We describe a closed-circuit Xe delivery system with automatic mechanical oxygen replenishment, which could be developed as a single use device. Gas exchange was maintained while Xe consumption was minimal (<$2/h at $10/L*). We have shown it is both feasible and cost-efficient to use this Xe delivery method in newborn pigs for up to 16 h with or without concurrent cooling after a severe HI insult.
Newborn encephalopathy represents a clinical syndrome with diverse causes, many of which may result in brain injury. Hypoxic-ischemic encephalopathy represents a subset of newborns with encephalopathy and, in contrast to other causes, may have a modifiable outcome. Laboratory research has demonstrated robust neuroprotection associated with reductions of brain temperature following hypoxia-ischemia in animals. The neuroprotective effects of hypothermia reflect antagonism of multiple cascades of events that contribute to brain injury. Clinical trials have translated laboratory observations into successful interventions. Hypoxicischemic encephalopathy is often unanticipated, unavoidable, and may occur in any obstetric setting. Pediatricians and other providers based in community hospitals play a critical role in the initial assessment, recognition, and stabilization of infants who may be candidates for therapeutic hypothermia.
In this article, the role of hypothermia and neuroprotection for neonatal encephalopathy will be discussed. The incidence of encephalopathy due to hypoxia ischemia as well as the pathophysiology will be presented. The diagnosis of encephalopathy in full-term neonates will be discussed. The current management of brain injury that occurs with hypoxia ischemia and the role of hypothermia in preventing brain injury in fetal and neonatal animal models will be reviewed. The current data from randomized control trials of hypothermia as neuroprotection for full-term infants will be presented along with the results of meta-analyses of these trials. Lastly, the status of ongoing neonatal hypothermia trials will be summarized.
We hypothesized that pretreatment with docosahexaenoic acid (DHA), a potentially neuroprotective polyunsaturated fatty acid, would improve function and reduce brain damage in a rat model of perinatal hypoxia-ischemia.
Seven-day-old rats were divided into 3 treatment groups that received intraperitoneal injections of DHA 1, 2.5, or 5 mg/kg as DHA-albumin complex and 3 controls that received 25% albumin, saline, or no injection. Subsequently, rats underwent right carotid ligation followed by 90 minutes of 8% oxygen. Rats underwent sensorimotor testing (vibrissae-stimulated forepaw placing) and morphometric assessment of right-sided tissue loss on postnatal day 14.
DHA pretreatment improved forepaw placing response to near-normal levels (9.5 +/- 0.9 treatment vs 7.1 +/- 2.2 controls; normal = 10; P < .0001). DHA attenuated hemisphere damage compared with controls (P = .0155), with particular benefit in the hippocampus with 1 mg/kg (38% protection vs albumin controls).
DHA pretreatment improves functional outcome and reduces volume loss after hypoxia-ischemia in neonatal rats.
The object of this review was to determine the incidence, morbidity, and mortality of an umbilical arterial pH < 7.0; the incidence of hypoxic-ischemic encephalopathy; and the proportion of cerebral palsy associated with intrapartum hypoxia-ischemia in nonanomalous term infants. A systematic review of the English language literature on the association between intrapartum hypoxia-ischemia and neonatal encephalopathy was conducted by using Pubmed and Embase. For nonanomalous term infants, the incidence of an umbilical arterial pH < 7.0 at birth is 3.7 of 1000, of which 51 of 297 (17.2%) survived with neonatal neurologic morbidity, 45 of 276 (16.3%) had seizures, and 24 of 407 (5.9%) died during the neonatal period. The incidence of neonatal neurologic morbidity and mortality for term infants born with cord pH < 7.0 was 23.1%. The incidence of hypoxic-ischemic encephalopathy is 2.5 of 1000 live births. The proportion of cerebral palsy associated with intrapartum hypoxia-ischemia is 14.5%. The vast majority of cases of cerebral palsy in nonanomalous term infants are not associated with intrapartum hypoxia-ischemia.
We are entering an era in which hypothermia will be used in combination with other novel neuroprotective interventions. The targeting of multiple sites in the cascade leading to brain injury may prove to be a more effective treatment strategy after hypoxic-ischemic encephalopathy in newborn infants than hypothermia alone.
Twenty-one neonates of over 36 weeks' gestation suffered perinatal asphyxia but not chronic hypoxia. Three clinical stages of postanoxic encephalopathy were distinguished. Stage 1 lasted less than 24 hours and was characterized by hyperalertness, uninhibited Moro and stretch reflexes, sympathetic effects, and a normal electroencephalogram. Stage 2 was marked by obtundation, hypotonia, strong distal flexion, and multifocal seizures. The EEG showed a periodic pattern sometimes preceded by continuous delta activity. Infants in stage 3 were stuporous, flaccid, and brain stem and autonomic functions were suppressed. The EEG was isopotential or had infrequent periodic discharges. Infants who did not enter stage 3 and who had signs of stage 2 for less than five days appeared normal in later infancy. Persistence of stage 2 for more than seven days or failure of the EEG to revert to normal was associated with later neurologic impairment or death.
Phosphorous (31P) spectra from the brains of severely birth-asphyxiated human infants are commonly normal on the first day of life. Later, cerebral energy failure develops, which carries a serious prognosis. The main purpose of this study was to test the hypothesis that this delayed ("secondary") energy failure could be reproduced in the newborn piglet after a severe acute reversed cerebral hypoxic-ischemic insult. Twelve piglets were subjected to temporary occlusion of the common carotid arteries and hypoxemia [mean arterial PO2 3.1 (SD 0.6) kPa]. Mean cerebral phosphocreatine concentration [PCr]/inorganic orthophosphate concentration [Pi] decreased from 1.40 (SD 0.29) to 0.01 (SD 0.02), and nucleotide triphosphate concentration [NTP]/exchangeable phosphate pool concentration [EPP] decreased from 0.19 (SD 0.02) to 0.06 (SD 0.04) (p < 0.001 for each decrease). On reperfusion and reoxygenation of the brain, mean [PCr]/[Pi] and [NTP]/[EPP] returned to baseline. Observations continuing for the next 48 h showed that [PCr]/[Pi] again decreased, in spite of normal arterial PO2, mean arterial blood pressure, and blood glucose, to 0.62 (SD 0.61) at 24 h (p < 0.01) and 0.49 (SD 0.37) at 48 h (p < 0.001). [NTP]/[EPP] also decreased, but to a lesser degree. Intracellular pH remained unchanged. These findings appeared identical with those seen in birth-asphyxiated human infants. No changes in cerebral metabolite concentrations took place in six control piglets. The severity of secondary energy failure, as judged by the lowest [PCr]/[Pi] recorded at 24-48 h, was directly related to the extent of acute energy depletion, obtained as the time integral of reduction in [NTP]/[EPP] (p < 0.0001). This animal model of secondary energy failure may prove useful for testing cerebroprotective strategies.
To determine the practicality and safety of head cooling with mild or minimal systemic hypothermia in term neonates with moderate to severe hypoxic-ischemic encephalopathy.
Study group infants >/=37 weeks' gestation, who had an umbilical artery pH </=7. 09 or Apgars </=6 at 5 minutes, plus evidence of encephalopathy. Infants with major congenital abnormalities were excluded. TRAIL DESIGN: Infants were randomized to either no cooling (controls; rectal temperature = 37.0 +/- 0.2 degreesC, n = 10) or sequentially, either minimal systemic cooling (rectal temperature = 36.3 +/- 0.2 degreesC, n = 6) or mild systemic cooling (rectal temperature = 35.7 +/- 0.2 degreesC, n = 6). Head cooling was accomplished by circulating water at 10 degreesC through a coil of tubing wrapped around the head for up to 72 hours. All infants were warmed by servo-controlled overhead heaters to maintain the allocated rectal temperature. The rectal, fontanelle, and nasopharyngeal temperatures were continuously monitored.
From January 1996 to October 1997, 22 term infants were randomized from 2 to 5 hours after birth. All infants showed a metabolic acidosis at delivery, with similar umbilical artery pH in the control group (mean +/- standard deviation, 6.79 +/- 0.25), minimal cooling group (6.98 +/- 0.21), and mild cooling group (6.93 +/- 0.11), and depressed Apgar scores at 5 minutes in the control group (4.5 +/- 2), minimal cooling group, (4.7 +/- 2) and mild cooling group (6.0 +/- 1). In the mild-cooled infants, the nasopharyngeal temperature was 34.5 degreesC during cooling, 1.2 degreesC lower than the rectal temperature. This gradient narrowed to 0.5 degreesC after cooling was stopped. No adverse effects because of cooling were observed. No infants developed cardiac arrhythmias, hypotension, or bradycardia during cooling. Thrombocytopenia occurred in 2 out of 10 controls, 2 out of 6 minimal cooling infants, and 1 out of 6 mild cooling infants. Hypoglycemia (glucose <2.6 mM) was seen on at least one occasion in 2 out of 10 controls, 4 out of 6 minimal cooling infants, and 1 out of 6 mild cooling infants. Acute renal failure occurred in all infants. The metabolic acidosis present in all infants at the time of enrollment into the study progressively resolved despite cooling, even in the mild hypothermia group.
Mild selective head cooling combined with mild systemic hypothermia in term newborn infants after perinatal asphyxia is a safe and convenient method of quickly reducing cerebral temperature with an increased gradient between the surface of the scalp and core temperature. The safety of mild hypothermia with selective head cooling is in contrast with the historical evidence of adverse effects with greater depths of whole-body hypothermia. This safety study and the strong experimental evidence for improved cerebral outcome justify a multicenter trial of selective head cooling for neonatal encephalopathy in term infants.
Since the discovery that the gas xenon can produce general anaesthesia
without causing undesirable side effects, we have remained surprisingly
ignorant of the molecular mechanisms underlying this clinical activity
of an `inert' gas. Although most general anaesthetics enhance the
activity of inhibitory GABAA (γ-aminobutyric acid
type-A) receptors,, we find that the effects of xenon on these receptors
are negligible. Instead, xenon potently inhibits the excitatory NMDA
(N-methyl-D-aspartate) receptor channels, which may account for many of
xenon's attractive pharmacological properties.
Hydrogen peroxide (H2O2) has previously been shown to inhibit the DNA binding activity of hypoxia inducible factor-1 (HIF-1), the accumulation of HIF-1alpha protein and erythropoietin (Epo) gene expression. Epo gene expression has been previously shown to be down-regulated through a GATA binding site at its promoter region. In this study, the effect of H2O2 on Epo gene expression under hypoxic conditions through a GATA transcription factor was investigated. Hypoxic induction was found to be inhibited upon the addition of H2O2, and this effect could be reversed through the addition of catalase. Hypoxic induction was found to be suppressed by co-transfection with a human GATA-2 cDNA expression plasmid. Transfection of Hep3B cells with a reporter gene bearing a mutation at the promoter GATA binding site was found to be only mildly affected by the addition of H2O2. Electrophoretic gel mobility shift assays (EMSAs), using the Epo promoter GATA site as a probe and the GATA-2 protein extracted from Hep3B cells, showed that addition of H2O2 enhanced the binding of GATA-2 while addition of catalase inhibited this binding. From these results, we conclude that H2O2 increases the binding activity of GATA-2 in a specific manner, thereby suppressing the activity of the Epo promoter and thus inhibiting Epo gene expression.