Neuroprotective Agents for Neonates with Hypoxic-Ischemic Encephalopathy

2021 ◽  
Vol 40 (6) ◽  
pp. 406-413
Author(s):  
Keliana O'Mara ◽  
Christopher McPherson
Keyword(s):  
Therapeutic Hypothermia ◽  
Ischemic Injury ◽  
Hypoxic Ischemic Encephalopathy ◽  
Neuroprotective Agents ◽  
Neuroprotective Effects ◽  
Animal Data ◽  
Neurodevelopmental Impairment ◽  
Pharmacologic Agents ◽  
Ischemic Encephalopathy

Hypoxic-ischemic encephalopathy (HIE) remains a significant source of long-term neurodevelopmental impairment despite overall improvements in survival without disability in neonates who undergo therapeutic hypothermia. Each phase in the evolution of hypoxic-ischemic injury presents potential pharmacologic targets for neuroprotective agents. Melatonin is a promising emerging therapy for early phases of ischemic injury, but utility is currently limited by the lack of pharmaceutical-grade products. Magnesium has been extensively studied for its neuroprotective effects in the preterm population. Studies in neonates with HIE have produced mixed outcomes. Erythropoietin use in HIE with or without therapeutic hypothermia appears to be safe and may provide additional benefit. Dexmedetomidine, N-acetylcysteine, xenon, and topiramate all have promising animal data, but need additional human trials to elucidate what role they may play in HIE. Frequent review of existing literature is required to ensure provision of evidence-based pharmacologic agents for neuroprotection following HIE.

Current Practice of Therapeutic Hypothermia for Mild Hypoxic Ischemic Encephalopathy

2019 ◽  
Vol 34 (7) ◽  
pp. 402-409 ◽  
Author(s):  
Chia L. Saw ◽  
Abhijeet Rakshasbhuvankar ◽  
Shripada Rao ◽  
M Bulsara ◽  
Sanjay Patole
Keyword(s):  
Adverse Effects ◽  
Therapeutic Hypothermia ◽  
Meta Analysis ◽  
Significant Proportion ◽  
Small Sample ◽  
Hypoxic Ischemic Encephalopathy ◽  
Cochrane Library ◽  
Short And Long Term ◽  
Ischemic Encephalopathy

Context: Therapeutic hypothermia is the recommended treatment for neonates with moderate or severe hypoxic ischemic encephalopathy (HIE). There is an increasing trend to use therapeutic hypothermia even in infants with mild hypoxic ischemic encephalopathy, even though there is little evidence to support/refute this. Objective: To estimate the incidences of mild hypoxic ischemic encephalopathy among infants who received therapeutic hypothermia, and its short- and long-term outcomes. Data Sources and Study Selection: PubMed, Embase, CINAHL, and Cochrane library were searched to identify observational studies reporting on therapeutic hypothermia in term and near-term infants with mild hypoxic ischemic encephalopathy. The JBI (Joanna Briggs Institute) tools were used to assess the risk of bias in the included studies. Random effects meta-analysis was conducted to find out the percentage of cooled infants who had only mild hypoxic ischemic encephalopathy. Results: A total of 3590 citations were screened, of which 13 were included. Of the 2783 infants who received therapeutic hypothermia, 573 had mild hypoxic ischemic encephalopathy. Meta-analysis found that 22% of the infants who underwent therapeutic hypothermia had only mild hypoxic ischemic encephalopathy (95% confidence interval: 16%-27%; I2 statistic = 90.5%). Five studies provided information on adverse effects of therapeutic hypothermia in mild hypoxic ischemic encephalopathy. The reported adverse effects were extreme hypothermia, bradycardia, hypoglycemia, sepsis, skin necrosis, pulmonary hypertension, and systemic hypotension. Limitation: The limitations included relatively small sample size and the lack of data for short- and long-term neurodevelopmental outcome. Conclusions: A significant proportion of infants who received therapeutic hypothermia had mild hypoxic ischemic encephalopathy. Randomized trials are urgently needed to evaluate the efficacy and safety of therapeutic hypothermia in infants with mild hypoxic ischemic encephalopathy.

Predictors of Long-Term Neurodevelopmental Outcome of Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia

2020 ◽  
Vol 40 (03) ◽  
pp. 322-334
Author(s):  
Ipsita Goswami ◽  
Mireille Guillot ◽  
Emily W. Y. Tam
Keyword(s):  
Brain Injury ◽  
Therapeutic Hypothermia ◽  
Prognostic Markers ◽  
Neurodevelopmental Outcome ◽  
Hypoxic Ischemic Encephalopathy ◽  
Secondary Brain Injury ◽  
Prognostic Utility ◽  
Initial Injury ◽  
Ischemic Encephalopathy

AbstractHypoxic-ischemic encephalopathy (HIE) is a manifestation of perinatal asphyxial insult that continues to evolve over days to weeks following the initial injury. Therapeutic hypothermia has demonstrated that a proportion of this secondary brain injury may indeed be preventable. However, therapeutic hypothermia has also altered the prognostic utility of many bedside tools that are commonly used as predictors of long-term neurodevelopmental outcome in HIE. Clinicians are often confronted with uncertainty when assessing the prognosis of infants with HIE. Improved understanding of the implications and limitations of individual investigations may inform clinical decisions and allow for timely intervention. This review summarizes the predictive value of currently available prognostic markers in HIE infants in the therapeutic hypothermia era, including clinical, biochemical, neurophysiological, physiological, and neuroimaging predictors.

scholarly journals Long-Term Outcomes after Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Therapeutic Hypothermia: A Longitudinal, Prospective, Multicenter Case-Control Study in Children without Overt Brain Damage

Children ◽  
2021 ◽  
Vol 8 (11) ◽  
pp. 1076
Author(s):  
Elisa Cainelli ◽  
Luca Vedovelli ◽  
Emmanuele Mastretta ◽  
Dario Gregori ◽  
Agnese Suppiej ◽  
...  
Keyword(s):  
Executive Functions ◽  
Therapeutic Hypothermia ◽  
Parental Stress ◽  
Neuropsychological Functioning ◽  
Hypoxic Ischemic Encephalopathy ◽  
Sample Population ◽  
Long Term Outcomes ◽  
Visuomotor Skills ◽  
Ischemic Encephalopathy

Background. Data on long-term outcomes in the era before therapeutic hypothermia (TH) showed a higher incidence of cognitive problems. Since the introduction of TH, data on its results are limited. Methods. Our sample population consisted of 40 children with a history of hypoxic-ischemic encephalopathy (HIE) treated with TH, with an average age of 6.25 years (range 5.5, 7.33), 24 (60%) males; and 33 peers with an average age of 8.8 years (6.08, 9.41), 17 (51%) males. Long-term follow-up data belong to two centers in Padova and Torino. We measured general intelligence (WPPSI-III or WISC-IV) and neuropsychological functioning (language, attention, memory, executive functions, social skills, visual motor abilities). We also administered questionnaires to their parents on the children’s psychopathological profiles and parental stress. Results. We found differences between groups in several cognitive and neuropsychological domains: intelligence, visuomotor skills, executive functions, and attention. Interestingly, IQ test results effectively differentiated between the groups (HIE vs. controls). Furthermore, the incidence of psychopathology appears to be significantly higher in children with HIE (35%) than in control peers (12%). Conclusions. Our study supports previous findings on a higher incidence of neuropsychological, cognitive, and psychopathological sequelae after HIE treated with TH. As hypothesized, TH does not appear to ameliorate the outcome after neonatal HIE in those children who survive without major sequelae.

scholarly journals Scutellarin ameliorates neonatal hypoxic-ischemic encephalopathy associated with GAP43-dependent signaling pathway

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rui-Ze Niu ◽  
Liu-Lin Xiong ◽  
Hao-Li Zhou ◽  
Lu-Lu Xue ◽  
Qing-Jie Xia ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Ischemic Injury ◽  
Hypoxic Ischemic Encephalopathy ◽  
Qrt Pcr ◽  
Pharmacological Analysis ◽  
Ischemic Encephalopathy ◽  
Hypoxic Ischemic Injury

Abstract Background Neonatal hypoxic-ischemic encephalopathy (HIE) refers to the perinatal asphyxia caused by the cerebral hypoxic-ischemic injury. The current study was aimed at investigating the therapeutic efficacy of Scutellarin (Scu) administration on neurological impairments induced by hypoxic-ischemic injury and exploring the underlying mechanisms. Methods Primary cortical neurons were cultured and subjected to oxygen–glucose deprivation (OGD), and then treated with Scu administration. The growth status of neurons was observed by immunofluorescence staining of TUJ1 and TUNEL. Besides, the mRNA level of growth-associated protein 43 (GAP43) in OGD neurons with Scu treatment was detected by quantitative real-time polymerase chain reaction (qRT-PCR). To further verify the role of GAP43 in Scu treatment, GAP43 siRNA and knockout were applied in vitro and in vivo. Moreover, behavioral evaluations were performed to elucidate the function of GAP43 in the Scu-ameliorated long-term neurological impairments caused by HI insult. The underlying biological mechanism of Scu treatment was further elucidated via network pharmacological analysis. Finally, the interactive genes with GAP43 were identified by Gene MANIA and further validated by qRT-PCR. Results Our data demonstrated that Scu treatment increased the number of neurons and axon growth, and suppressed cell apoptosis in vitro. And the expression of GAP43 was downregulated after OGD, but reversed by Scu administration. Besides, GAP43 silencing aggravated the Scu-ameliorated neuronal death and axonal damage. Meanwhile, GAP43 knockout enlarged brain infarct area and deteriorated the cognitive and motor dysfunctions of HI rats. Further, network pharmacological analysis revealed the drug targets of Scu participated in such biological processes as neuronal death and regulation of neuronal death, and apoptosis-related pathways. GAP43 exhibited close relationship with PTN, JAK2 and STAT3, and GAP43 silencing upregulated the levels of PTN, JAK2 and STAT3. Conclusions Collectively, our findings revealed Scu treatment attenuated long-term neurological impairments after HI by suppressing neuronal death and enhancing neurite elongation through GAP43-dependent pathway. The crucial role of Scutellarin in neuroprotection provided a novel possible therapeutic agent for the treatment of neonatal HIE. Graphic abstract

scholarly journals Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a National Survey in China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zheng Wang ◽  
Peng Zhang ◽  
Wenhao Zhou ◽  
Shiwen Xia ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
National Survey ◽  
Diagnosis And Treatment ◽  
Hypoxic Ischemic Encephalopathy ◽  
Current Status ◽  
Significant Heterogeneity ◽  
National Guidelines ◽  
Neurodevelopmental Outcomes ◽  
Ischemic Encephalopathy

Abstract Background Neonatal 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. Method This 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. Results The 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. Conclusions There 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.

Case series of therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy during extracorporeal life support

Perfusion ◽  
2020 ◽  
Vol 35 (7) ◽  
pp. 700-706
Author(s):  
Prasad Bhandary ◽  
John M Daniel ◽  
Sean C Skinner ◽  
Matthew K Bacon ◽  
Mina Hanna ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
Life Support ◽  
Extracorporeal Life Support ◽  
Case Series ◽  
Standard Of Care ◽  
Hypoxic Ischemic Encephalopathy ◽  
Short Term ◽  
Ischemic Encephalopathy

Therapeutic hypothermia initiated within 6 hours of birth is currently the standard of care for the management of neonates with hypoxic-ischemic encephalopathy. Neonates undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy are also at risk for severe respiratory failure and need for extracorporeal life support. The risks and benefits of therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support are still not well defined. We report our experience of a case series of six neonates who underwent therapeutic hypothermia for hypoxic-ischemic encephalopathy during extracorporeal life support. We also report long-term neurodevelopmental follow-up from 6 to 24 months and add to the current body of evidence regarding feasibility, clinical experience, and short-term complications.

scholarly journals Neonatal Hypoxic-Ischemic Encephalopathy Diagnosis and Treatment: A National Survey in China

2021 ◽  
Author(s):  
Zheng Wang ◽  
Peng Zhang ◽  
Wenhao Zhou ◽  
Shiwen Xia ◽  
Wei Zhou ◽  
...  
Keyword(s):  
Therapeutic Hypothermia ◽  
National Survey ◽  
Diagnosis And Treatment ◽  
Hypoxic Ischemic Encephalopathy ◽  
Current Status ◽  
Significant Heterogeneity ◽  
National Guidelines ◽  
Neurodevelopmental Outcomes ◽  
Ischemic Encephalopathy

Abstract Background: Neonatal 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. Method: This 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. Results: The 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 ten 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. Conclusions: There 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.

Visual outcomes in children with neonatal hypoxic ischemic encephalopathy treated with therapeutic hypothermia

2021 ◽  
Author(s):  
Jerry Hsu ◽  
Noreen Shaikh ◽  
Hantamalala Ralay Ranaivo ◽  
Andrea C. Pardo ◽  
Rebecca B. Mets-Halgrimson
Keyword(s):  
Therapeutic Hypothermia ◽  
Hypoxic Ischemic Encephalopathy ◽  
Visual Outcomes ◽  
Ischemic Encephalopathy

scholarly journals The Kynurenic Acid Analog SZR72 Enhances Neuronal Activity after Asphyxia but Is Not Neuroprotective in a Translational Model of Neonatal Hypoxic Ischemic Encephalopathy

2021 ◽  
Vol 22 (9) ◽  
pp. 4822
Author(s):  
Viktória Kovács ◽  
Gábor Remzső ◽  
Tímea Körmöczi ◽  
Róbert Berkecz ◽  
Valéria Tóth-Szűki ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Kynurenic Acid ◽  
Neuronal Damage ◽  
Brain Regions ◽  
Hypoxic Ischemic Encephalopathy ◽  
Hippocampal Field ◽  
Power Spectral ◽  
Density Values ◽  
Ischemic Encephalopathy

Hypoxic–ischemic encephalopathy (HIE) remains to be a major cause of long-term neurodevelopmental deficits in term neonates. Hypothermia offers partial neuroprotection warranting research for additional therapies. Kynurenic acid (KYNA), an endogenous product of tryptophan metabolism, was previously shown to be beneficial in rat HIE models. We sought to determine if the KYNA analog SZR72 would afford neuroprotection in piglets. After severe asphyxia (pHa = 6.83 ± 0.02, ΔBE = −17.6 ± 1.2 mmol/L, mean ± SEM), anesthetized piglets were assigned to vehicle-treated (VEH), SZR72-treated (SZR72), or hypothermia-treated (HT) groups (n = 6, 6, 6; Tcore = 38.5, 38.5, 33.5 °C, respectively). Compared to VEH, serum KYNA levels were elevated, recovery of EEG was faster, and EEG power spectral density values were higher at 24 h in the SZR72 group. However, instantaneous entropy indicating EEG signal complexity, depression of the visual evoked potential (VEP), and the significant neuronal damage observed in the neocortex, the putamen, and the CA1 hippocampal field were similar in these groups. In the caudate nucleus and the CA3 hippocampal field, neuronal damage was even more severe in the SZR72 group. The HT group showed the best preservation of EEG complexity, VEP, and neuronal integrity in all examined brain regions. In summary, SZR72 appears to enhance neuronal activity after asphyxia but does not ameliorate early neuronal damage in this HIE model.

Sign in / Sign up

Export Citation Format

Share Document