Potential use of lactate for the treatment of neonatal hypoxic-ischemic encephalopathy.
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SUBMITTER: Tassinari ID
PROVIDER: S-EPMC8530120 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectiveHypoxic-ischemic encephalopathy (HIE) is a leading cause of death and disability worldwide. Therapeutic hypothermia (TH) represents a significant achievement in the translation of scientific research to clinical application, but it is currently the only neuroprotective treatment for HIE. This review aims to revisit the use of TH for HIE and its longitudinal impact on patient outcomes to readers new to the field of HIE. We discuss how emerging therapies address the broader pathophysiology of injury progression in the neonatal brain days to years after HIE.MethodsWe included full articles and book chapters published in English on PubMed with references to "hypoxic ischemic encephalopathy", "birth asphyxia", "therapeutic hypothermia", or "neonatal encephalopathy". We limited our review to outcomes on term infants and to new therapeutics that are in the second phase of clinical trials.Key content and findingsDespite the use of TH for HIE, mortality remains high. Analysis of longitudinal studies reveals a high incidence of ongoing disability even with the implementation of TH. New therapeutics addressing the secondary phase and the less understood tertiary phase of brain injury are in clinical trials as adjunctive treatments to TH to support additional neurological repair and regeneration.ConclusionsTH successfully improves outcomes after HIE, and it continues to be optimized. Larger studies are needed to understand its use in mild cases of HIE and if certain factors, such as sex, affect long term outcomes. TH primarily acts in the initial phases of injury, while new pharmaceutical therapies target additional injury pathways into the tertiary phases of injury. This may allow for more effective approaches to treatment and improvement of long-term functional outcomes after HIE.
| S-EPMC10485647 | biostudies-literature
Project description:Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. We will identify understudied targets after HIE, as well as neuroprotective molecules that bring hope to future treatments such as melatonin, topiramate, xenon, interferon-beta, stem cell transplantation. This review will also discuss some of the most recent trials being conducted in the clinical setting and evaluate what directions are needed in the future.
| S-EPMC4613313 | biostudies-literature
Project description:Introduction Neonatal hypoxic-ischemic encephalopathy (NHIE) is a common neurologic injury, and it may compromise the child's language and cognition. Understanding the process of language acquisition becomes possible with concise knowledge about children's global development. Objective The aim of this study was to observe if language acquisition and development are impaired in children with NHIE. Methods Seventy children with NHIE from 1 to 24 months old were analyzed in a Pediatric Neurology Service of Hospital of Porto Alegre, South of Brazil using the Brunet-Lezine Scale. Statistical analysis used SPSS 13.0 software. Results Twenty-four (60%) of the subjects were boys, with mean gestational age of 35.8 weeks (standard deviation of 4.6) and mean Apgar score of 6.0 at 1 minute and 7.1 at 5 minutes. The variables age versus language showed significant inverse correlation (r = - 0.566; p = 0.028). As the subjects aged, language tasks became more specific and dependent on the subject's direct action, rather than the subjective interpretation of their guardian. This correlation seems to be closely associated with scale configuration and with consequences of neurologic disorder, evincing the delays in language development. Conclusion This study achieved the goals proposed and highlights the necessity of greater attention by professionals to language skills during the initial period of child development.
| S-EPMC4297029 | biostudies-other
Project description:Background: Therapeutic hypothermia (TH) is the standard therapy for hypoxic-ischemic encephalopathy (HIE) and is associated with a wide range of physiological changes. Objective: We re-evaluated the effects of HIE and TH on bilirubin measurements following HIE in a center involved in the China cooling randomized controlled trial (RCT). Methods: Serial serum bilirubin concentrations measured during the first week of life were compared among the HIE + NT (normothermia) group, HIE + TH treatment group and control group (without HIE). Survivors of HIE were followed and assessed at approximately 2 years of age, and the results were correlated with peak bilirubin levels during the first week of life. Results: One hundred and thirty-eight infants were available for analysis. Significantly lower bilirubin levels were recorded in the HIE + NT group than in the controls (P<0.05). Significant differences were not observed among the patients in the HIE + NT group (mild to severe) or between the HIE + TH group and the HIE + NT group at any time point (P>0.05). The peak serum bilirubin concentrations recorded at 96 h of age showed a good correlation with the results of the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) (P=0.02). Conclusion: Bilirubin potentially exerts a neuroprotective effect during the first week of life, and low temperature does not affect the possible antioxidant function of bilirubin during TH following HIE.
| S-EPMC6549084 | biostudies-literature
Project description:BackgroundNeonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China.MethodThis prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher's exact test were used, and a p-value of < 0.05 was considered significant.ResultsThe 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) (χ2 = 11.752, p = 0.001) and children's hospitals (77%, 27/35) (χ2 = 13.446, p < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE.ConclusionsThere is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.
| S-EPMC8178820 | biostudies-literature
Project description:BackgroundVitamin D has neuroprotective and immunomodulatory properties, and deficiency is associated with worse stroke outcomes. Little is known about effects of hypoxia-ischemia or hypothermia treatment on vitamin D status in neonates with hypoxic-ischemic encephalopathy (HIE). We hypothesized vitamin D metabolism would be dysregulated in neonatal HIE altering specific cytokines involved in Th17 activation, which might be mitigated by hypothermia.MethodsWe analyzed short-term relationships between 25(OH) and 1,25(OH)2 vitamin D, vitamin D binding protein, and cytokines related to Th17 function in serum samples from a multicenter randomized controlled trial of hypothermia 33 °C for 48 h after HIE birth vs. normothermia in 50 infants with moderate to severe HIE.ResultsInsufficiency of 25(OH) vitamin D was observed after birth in 70% of infants, with further decline over the first 72 h, regardless of treatment. 25(OH) vitamin D positively correlated with anti-inflammatory cytokine IL-17E in all HIE infants. However, Th17 cytokine suppressor IL-27 was significantly increased by hypothermia, negating the IL-27 correlation with vitamin D observed in normothermic HIE infants.ConclusionSerum 25(OH) vitamin D insufficiency is present in the majority of term HIE neonates and is related to lower circulating anti-inflammatory IL-17E. Hypothermia does not mitigate vitamin D deficiency in HIE.
| S-EPMC5509506 | biostudies-literature
Project description:To examine the predictive ability of stage of hypoxic-ischemic encephalopathy (HIE) for death or moderate/severe disability at 18 months among neonates undergoing hypothermia.Stage of encephalopathy was evaluated at <6 hours of age, during study intervention, and at discharge among 204 participants in the National Institute of Child Health and Human Development Neonatal Research Network Trial of whole body hypothermia for HIE. HIE was examined as a predictor of outcome by regression models.Moderate and severe HIE occurred at <6 hours of age among 68% and 32% of 101 hypothermia group infants and 60% and 40% of 103 control group infants, respectively. At 24 and 48 hours of study intervention, infants in the hypothermia group had less severe HIE than infants in the control group. Persistence of severe HIE at 72 hours increased the risk of death or disability after controlling for treatment group. The discharge exam improved the predictive value of stage of HIE at <6 hours for death/disability.On serial neurologic examinations, improvement in stage of HIE was associated with cooling. Persistence of severe HIE at 72 hours and an abnormal neurologic exam at discharge were associated with a greater risk of death or disability.
| S-EPMC3299861 | biostudies-other
Project description:ObjectiveTo define similarities and differences between neonatal arterial ischemic stroke (NAIS) and hypoxic-ischemic neonatal encephalopathy (HINE).MethodsA retrospective case-control study was conducted of neonates born at 35 weeks or more and weighing 1800 g or more at a tertiary care university hospital, between 2005 and 2016, with NAIS (group A), perinatal asphyxia (PA) with Stage II-III HINE (group B), and PA with or without Stage I HINE (group C). Ante- and intrapartum data, neonatal characteristics, and placental histopathology were compared.ResultsEleven neonates were identified in group A, 10 in group B, and 227 in group C. Sentinel events occurred exclusively in groups B (80%) and C (41.4%). Umbilical cord blood gas values and Apgar score were worse in groups B and C compared to group A. No group A neonates required resuscitation at birth, whereas all group B and one-third of group C neonates did. Seizures developed only in neonates in groups A and B. One neonatal death occurred in group A. There were no significant differences in placental histopathology.ConclusionNAIS and PA/HINE cases have different intrapartum and neonatal features. PA does not seem necessary for the occurrence of NAIS. More research is needed regarding associated placental abnormalities.
| S-EPMC9290624 | biostudies-literature
Project description:BackgroundFew studies on the consequences following newborn hypoxic-ischemic encephalopathy (NHIE) assess the risk of mood disorders (MD), although these are prevalent after ischemic brain injury in adults.ObjectiveTo study the presence of MD in children survivors of NHIE.Methods14 children survivors of NHIE treated with hypothermia and without cerebral palsy and 15 healthy children without perinatal complications were studied aged three to six years for developmental status (Ages and Stages Questionnaire 3 [ASQ-3]) and for socio-emotional status (Preschool Symptom Self-Report [PRESS] and Child Behavior Checklist [CBCL] 1.5-5 tests). Maternal depression was assessed using Montgomery-Asberg Depression Rating Scale (MADRS). Socio-economic factors such as parental educational level or monthly income were also studied.ResultsNHIE children did not present delay but scored worse than healthy children for all ASQ3 items. NHIE children showed higher scores than healthy children for PRESS as well as for anxious/depressive symptoms and aggressive behavior items of CBCL. In addition, in three NHIE children the CBCL anxious/depressive symptoms item score exceeded the cutoff value for frank pathology (P = 0.04 vs healthy children). There were no differences in the other CBCL items as well as in maternal MADRS or parental educational level or monthly income. Neither ASQ3 scores nor MADRS score or socio-economic factors correlated with PRESS or CBCL scores.ConclusionsIn this exploratory study children survivors of NHIE showed increased risk of developing mood disturbances, in accordance with that reported for adults after brain ischemic insults. Considering the potential consequences, such a possibility warrants further research.
| S-EPMC8797213 | biostudies-literature
Project description:Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44-53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known: • Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy. • Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New: • Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia. • There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.
| S-EPMC8897336 | biostudies-literature