Hypoxic-ischemic Encephalopathy Infants Research Articles

Single-Center Experience with Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy in Infants < 36 Weeks Gestation.

Hypoxic ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in neonates. Therapeutic hypothermia (TH) has improved outcomes and mortality in infants >36 weeks gestational age (GA) with moderate-to-severe HIE. There are limited data on the safety and efficacy of TH in preterm infants with HIE. This study describes our experience and examines the safety of TH in neonates <36 weeks' GA. A single center, retrospective study of preterm neonates born <36 weeks' GA with moderate-to-severe HIE and treated with TH, compared to a cohort of term neonates with HIE (≥37 weeks' GA), was conducted. The term cohort was matched for degree of background abnormality on EEG, sex, inborn vs. outborn status, and birth year. Medical records were reviewed for pregnancy and delivery complications, need for transfusion, sedation and antiseizure medications, electroencephalography and imaging findings, and in-hospital mortality. Forty-two neonates born at <36 weeks' GA with HIE received TH between 2005-2022. Data from 42 term neonates was analyzed for comparison. The average GA of the preterm cohort was 34.6 weeks and 39.3 weeks for the term cohort. Apgar scores, degree of acidosis, and need for blood product transfusions were similar between groups. Preterm infants were more likely to require inotropic support (55% vs 29%, p=0.026) and hydrocortisone (36% vs 12%, p=0.019) for hypotension. The proportion of infants without evidence of injury on MRI was similar in both groups: 43% vs. 50% in preterm and term infants, respectively. No significant difference was found in mortality between groups. In this single-center cohort, TH in preterm infants appears to be as safe as in term infants, with no significant increase in intracranial bleeds or mortality. Preterm infants more frequently required inotropes and steroids for hypotension. Further research is needed to determine efficacy of TH in preterm infants.

Altered resting-state functional connectivity in newborns with hypoxic ischemic encephalopathy assessed using high-density functional near-infrared spectroscopy

Hypoxic-ischemic encephalopathy (HIE) results from a lack of oxygen to the brain during the perinatal period. HIE can lead to mortality and various acute and long-term morbidities. Improved bedside monitoring methods are needed to identify biomarkers of brain health. Functional near-infrared spectroscopy (fNIRS) can assess resting-state functional connectivity (RSFC) at the bedside. We acquired resting-state fNIRS data from 21 neonates with HIE (postmenstrual age [PMA] = 39.96), in 19 neonates the scans were acquired post-therapeutic hypothermia (TH), and from 20 term-born healthy newborns (PMA = 39.93). Twelve HIE neonates also underwent resting-state functional magnetic resonance imaging (fMRI) post-TH. RSFC was calculated as correlation coefficients amongst the time courses for fNIRS and fMRI data, respectively. The fNIRS and fMRI RSFC maps were comparable. RSFC patterns were then measured with graph theory metrics and compared between HIE infants and healthy controls. HIE newborns showed significantly increased clustering coefficients, network efficiency and modularity compared to controls. Using a support vector machine algorithm, RSFC features demonstrated good performance in classifying the HIE and healthy newborns in separate groups. Our results indicate the utility of fNIRS-connectivity patterns as potential biomarkers for HIE and fNIRS as a new bedside tool for newborns with HIE.

Does base excess predict kidney injury in neonates with hypoxic-ischemic encephalopathy?

In neonates with hypoxic-ischemic encephalopathy (HIE), we studied the correlation between cord blood base excess (BE) and kidney function. Among 225 infants, 29 % had oliguria. BE levels differed significantly between oliguric and non-oliguric infants (p < 0.01), with a negative correlation to kidney injury (r = −0.544, p < 0.01). BE < −18 had 85 % specificity and 76 % sensitivity in predicting kidney injury (AUC = 0.88). These findings suggest BE as a valuable indicator of impending kidney injury in HIE infants, though underlying mechanisms may vary.

Troponin I, CK-MB, and inotropic score in hypoxic-ischemic encephalopathy and associated infant mortality

PurposeCardiovascular dysfunction is common in hypoxic-ischemic encephalopathy (HIE), which is one of the leading causes of multi-organ failure in neonates. We aimed to assess troponin I and creatine kinase myocardial band (CK-MB) levels, inotropic score (IS) in HIE patients, and their associations with HIE staging and mortality.MethodThe medical records of all HIE infants admitted to our unit between 2016 and 2018 were retrospectively analyzed. Demographic characteristics of the infants, seizures, anticonvulsive therapies, maximum inotrope doses, and the derived IS (dopamine dose [µg/kg/min] + dobutamine dose [µg/kg/min] + 100 × epinephrine dose [µg/kg/min]) and CK-MB and troponin-I levels obtained in the first six hours of life were compared according to HIE staging. Comparisons between survivors and non-survivors were made.ResultsThe study included data from 195 patients. Twenty-five patients were classified as stage 3, 116 as stage 2, and 54 as stage 1 HIE. Median Troponin-I, CK-MB level, and IS significantly differed by HIE staging (p < 0.01). The deceased infants had significantly higher median troponin I level [0.36 (0.02-3) vs. 0.16 (0.01–1.1) ng/ml; p = 0.006], median IS [20 (5-120) vs. 5 (5–10); p < 0.001], however, CK-MB values were comparable with survivors [129 (51–300) vs. 60.7 (31–300) ng/ml; p = 0.57]. The area under the curve was 0.93 for IS and 0.81 for Troponin I to predict mortality.ConclusionTroponin I, CK-MB, and IS could be successfully used as disease severity markers in HIE furthermore, troponin I and IS, are good predictors of mortality. These results need to be confirmed with larger prospective multi-center studies.

Interleukin-33 and Soluble ST2 Levels in Infants with Hypoxic-Ischemic Encephalopathy

Introduction: Interleukin (IL)-33 and its receptor ST2L play key roles in the IL-33/ST2 signaling pathway. Soluble ST2 (sST2) inhibits the proper function of IL-33. sST2 levels are increased in patients with several neurological diseases, but in infants with hypoxic-ischemic encephalopathy (HIE), IL-33 and sST2 levels have not been studied. This study aimed to investigate whether serum levels of IL-33 and sST2 are useful as biomarkers of HIE severity and prognostic factors for infants with HIE. Methods: Twenty-three infants with HIE and 16 controls (gestational age ≥36 weeks and ≥1,800 g birth weight) were enrolled in this study. Serum levels of IL-33 and sST2 were measured at <6 h, 1–2, 3, and 7 days of age. Hydrogen-1 magnetic resonance spectroscopy was performed, and ratios of peak integrals of lactate/N-acetylaspartate (Lac/NAA) were calculated as objective indicators of brain damage. Results: In the moderate and severe HIE, serum sST2 concentrations were increased and there was a good correlation between serum sST2 and HIE severity on days 1–2, whereas no variation was observed in serum IL-33. Serum sST2 levels were positively correlated with Lac/NAA ratios (Kendall’s rank correlation coefficient = 0.527, p = 0.024), and both sST2 and Lac/NAA ratios were significantly higher in HIE infants with neurological impairment (p = 0.020 and <0.001, respectively). Conclusions: sST2 may be a useful predictor of severity and later neurological outcomes in infants with HIE. Further investigation is required to elucidate the relationship between the IL-33/ST2 axis and HIE.

Hypothermia combined with neuroprotective adjuvants shortens the duration of hospitalization in infants with hypoxic ischemic encephalopathy: Meta-analysis.

Objective: Therapeutic hypothermia (TH) is the current standard of care for neonatal hypoxic-ischemic encephalopathy (HIE), yet morbidity and mortality remain significant. Adjuvant neuroprotective agents have been suggested to augment hypothermic-mediated neuroprotection. This analysis aims to identify the classes of drugs that have been used in combination with hypothermia in the treatment of neonatal HIE and determine whether combination therapy is more efficacious than TH alone. Methods: A systematic search of PubMed, Embase and Medline from conception through December 2022 was conducted. Randomized- and quasi-randomized controlled trials, observational studies and retrospective studies evaluating HIE infants treated with combination therapy versus TH alone were selected. Primary reviewers extracted information on mortality, neurodevelopmental impairment and length of hospitalization for meta-analyses. Effect sizes were pooled using a random-effects model and measured as odds ratio (OR) or mean difference (MD) where applicable, and 95% confidence intervals (CI) were calculated. Risk of bias was assessed using the tool from the Cochrane Handbook for Systematic Reviews of Interventions. Results: The search strategy collected 519 studies, 16 of which met analysis inclusion criteria. HIE infants totaled 1,288 infants from included studies, 646 infants received some form of combination therapy, while 642 received TH alone. GABA receptor agonists, NMDA receptor antagonists, neurogenic and angiogenic agents, stem cells, glucocorticoids and antioxidants were identified as candidate adjuvants to TH that have been evaluated in clinical settings compared to TH alone. Length of hospitalization was significantly reduced in infants treated with combination therapy (MD -4.81, 95% CI [-8.42. to -1.19], p = .009) compared to those treated with TH alone. Risk of mortality and neurodevelopmental impairment did not differ between combination therapy and TH alone groups. Conclusion: Compared to the current standard of care, administration of neuroprotective adjuvants with TH reduced the duration of hospitalization but did not impact the risk of mortality or neurodevelopmental impairment in HIE infants. Meta-analysis was limited by a moderate risk of bias among included studies and small sample sizes. This analysis highlights the need for preclinical trials to conduct drug development studies in hypothermic settings to identify relevant molecular targets that may offer additive or synergistic neuroprotection to TH, and the need for larger powered clinical trials to determine the dose and timing of administration at which maximal clinical benefits are observed for adjuvant neuroprotectants.

24 Persistent pulmonary hypertension and short-term neurological outcomes in infants with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia

Abstract Background Neonatal hypoxic ischemic encephalopathy (HIE) after perinatal asphyxia is a serious clinical condition that may result in permanent neurologic deficits or death. There is an increased incidence of persistent pulmonary hypertension of the newborn (PPHN) in asphyxiated infants. Due to the high disease burden of HIE, studying its altered cardiopulmonary hemodynamics might identify those patients at highest risk for adverse outcome early on. Objectives To investigate the relationship between severity of PPHN and the extent of short-term brain injury in infants with moderate to severe HIE who received therapeutic hypothermia (TH). Design/Methods Retrospective cohort study of 230 TH-treated HIE infants. PPHN was defined and graded clinically and based on echocardiography findings. The primary outcome was the presence of HIE changes on brain MRI and/or death within the first month of life according to the diagnosis and severity of PPHN. Secondary outcomes were the pattern of HIE on brain MRI; abnormal electroencephalogram (EEG) background, clinical, or electrographic seizures, or need for anti-ictal treatment; clinical and laboratory differences between HIE babies with and without PPHN. A logistic regression model was performed to identify PPHN severity as risk factor for moderate-to-severe brain injury or death. Results Brain injury was not found to be different between the two groups according to presence of PPHN whether clinically or based on echocardiography. However, the combined outcome of severe brain injury or death was higher in the clinical PPHN group vs non-PPHN (32.6 vs 22.8%, p=0.014), and early exit from TH due to severe PPHN was associated with the highest mortality (71.4%). Death was found to have a relationship with the severity of PPHN based on echocardiography, with the highest incidence in severe PPHN (36.0 vs 7.7% and 10.0% in the severe, moderate, and mild PPHN groups, respectively, p=0.002). Infants with clinical PPHN were sicker with higher ventilation needs and worse laboratory values compared to those without PPHN. None of the other outcomes were different among the two groups. Conclusion In infants with HIE treated with TH, PPHN was not associated with increased risk of brain injury as evident on MRI, nor clinical or electrographic seizure burden. However, mortality was higher in the most severe PPHN categories.

Perinatal Events and Outcomes Associated with Hypoxic-Ischemic Encephalopathy in Thailand: A Multicenter, Observational Study

Background: Risk factors for perinatal hypoxic-ischemic encephalopathy (HIE) differ across high- and low- or middle-income countries. Recent evidence from a randomized trial of therapeutic hypothermia (TH) suggests that the intervention should not be offered in the aforementioned countries because of higher mortality rates and associated morbidity. Objective: To investigate characteristics of infants of 35 weeks or more gestational age (GA) born with HIE and determine the short-term outcomes of recipients of TH. Materials and Methods: A multicenter, retrospective, chart review was conducted of infants with 5-minute Apgar scores of 5 or less admitted to the four tertiary centers in Thailand between 2013 and 2020. Events associated with perinatal hypoxia and outcomes were extracted. Results: The incidence of perinatal HIE was 0.8 per 1,000 livebirths. Among 225 HIE infants, 46.2% had metabolic acidosis, 58.1% experienced hypoxic events, and 92.8% required advanced resuscitation. Among 123 infants who met TH criteria, 83 (67.5%) were treated. The overall HIErelated mortality rate was 24.9%. TH recipients had a lower mortality rate than untreated infants at 32.5% versus 52.5%, respectively (p=0.03) with a relative risk of 0.62 (95% CI 0.40 to 0.95). The findings were comparable to the reports from high-income countries. Conclusion: To correctly select neonates for TH, increased HIE awareness, mandatory cord blood gas analysis, and country-wide dissemination of eligible criteria are necessary for timely intervention. Keywords: Middle-income country; Encephalopathy; Risk factors; Hypoxic-ischemia; Therapeutic hypothermia

Early predictors of abnormal MRI patterns in asphyxiated infants: S100B protein urine levels.

The early detection and stratification of asphyxiated infants at higher risk for impaired neurodevelopment is challenging. S100B protein is a well-established biomarker of brain damage, but lacks conclusive validation according to the "gold standard" methodology for hypoxic-ischemic encephalopathy (HIE) prognostication, i.e. brain MRI. The aim of the present study was to investigate the predictive role of urinary S100B concentrations, assessed in a cohort of HIE infants receiving therapeutic hypothermia (TH), compared to brain MRI. Assessment of urine S100B concentrations was performed by immunoluminometric assay at first void and at 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120-h after birth. Neurologic evaluation, routine laboratory parameters, amplitude-integrated electroencephalography, and cerebral ultrasound were performed according to standard protocols. Brain MRI was performed at 7-10days of life. Overall, 74 HIE neonates receiving TH were included in the study. S100B correlated, already at first void, with the MRI patterns with higher concentrations in infants with the most severe MRI lesions. High S100B urine levels soon after birth constitute trustable predictors of brain injury as confirmed by MRI. Results support the reliability of S100B in clinical daily practice and open the way to its inclusion in the panel of parameters used for the selection of cases suitable for TH treatment.

Predictive Value of Heat-Shock Protein Gene Expression on Severe Neonatal Hypoxic-Ischemic Encephalopathy

This study aims to evaluate significant gene expression in severe hypoxic ischemic encephalopathy (HIE) in newborns, which can be used as a predictable measure for high-risk HIE infants. The study prospectively recruited 77 inborn near-term or term HIE newborns between January 2018 and December 2020. We measured six different genes within 6 h of life among the HIE infants and compared the gene levels between the mild- and severe-HIE groups. Among these, 64 HIE infants (83.1%) did not receive therapeutic hypothermia (TH) because they were categorized as mild HIE, and the 13 remaining (16.9%) infants were categorized as ≥ moderate-HIE group and received TH. More abnormal MRI findings, seizure, and use of anti-convulsant were more found in the ≥ moderate = HIE group along with longer mechanical ventilation days and hospitalization. Heat-shock protein 70 family 1 A (HSPA1A) and serpin family H member 1 (SERPINH1) genes, which encode heat-shock protein (HSP) 70 and 47, respectively, were significantly elevated in the ≥ moderate-HIE, seizure, and abnormal MRI groups. HSP 70 and 47 were significantly elevated in the severe-HIE group, possibly playing protective roles in inhibiting exacerbated neuroinflammation and maintaining a cellular homeostasis. At 18–24 months, ≥ moderate-HIE group manifested a significant language delay.

CSF neopterin and beta-2-microglobulin as inflammation biomarkers in newborns with hypoxic-ischemic encephalopathy.

Inflammation plays a crucial role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE). The aim of this study was to measure inflammation in HIE through an analysis of CSF neopterin and β2-microglobulin and to study the association with brain injury as shown by MRI findings and neurodevelopmental outcomes. CSF biomarkers were measured in study patients at 12 and 72 h. Brain injury was evaluated by MRI, and neurodevelopmental outcomes were assessed at 2-3 years of life. An adverse outcome was defined as the presence of motor or cognitive impairment. Sixty-nine HIE infants were included. Median values of neopterin and β2-microglobulin paralleled the severity of HIE. Adverse outcomes were associated with early neopterin and β2-microglobulin values, late neopterin values, and the neopterin percentage change between the two samples. A cutoff value of 75% neopterin change predicted adverse outcomes with a specificity of 0.9 and a sensitivity of 0.75. CSF neopterin and β2-microglobulin are elevated in HIE, indicating the activation of inflammation processes. Infants with adverse neurodevelopmental outcomes show higher levels of CSF neopterin and β2-microglobulin. The evolution of neopterin levels provides a better predictive capacity than a single determination. Brain inflammation in newborns with HIE could be measurable through the analysis of CSF neopterin and β2-microglobulin, both of which are associated with neurodevelopmental outcomes. Our study introduces two inflammatory biomarkers for infants with HIE that seem to show a more stable profile and are easier to interpret than cytokines. CSF neopterin and β2-m may become clinical tools to monitor inflammation in HIE and might eventually be helpful in measuring the response to emerging therapies.

153 Cost of Hospitalization in Infants with Hypoxic Ischemic Encephalopathy Treated with Therapeutic Hypothermia in a Quebec Tertiary Neonatal Intensive Care Unit and Validation of the Canadian Neonatal Network Costing Algorithm

Abstract Primary Subject area Neonatal-Perinatal Medicine Background Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxic ischemic encephalopathy (HIE) to improve mortality and long-term impairment. Accurate costing algorithms are essential to evaluate cost-effective interventions and identify cost drivers. Objectives We aimed to validate the Canadian Neonatal Network (CNN) costing algorithm for HIE infants treated with TH against costs obtained from hospital-based finance software (CPSS) and compare the costs of TH for infants with mild/moderate to those with severe HIE. We aimed to validate the Canadian Neonatal Network (CNN) costing algorithm for HIE infants treated with TH against costs obtained from hospital-based finance software (CPSS) and compare the costs of TH for infants with mild/moderate to those with severe HIE. Design/Methods Retrospective cohort study including 98 infants admitted with HIE and receiving TH in a tertiary NICU between 2016 and 2018. Clinical characteristics and CNN costing data were collected from the local CNN database and actual cost were obtained from CPSS. The primary outcome was the difference in total hospital stay cost between CNN algorithm and CPSS. The differences between both algorithms were also identified in 8 different cost centres such as nursing, respiratory, imaging, etc. Costs per patients using both algorithms were compared using Pearson correlation coefficient (r) and paired t-test. Characteristics and costs per infant were compared between infants with mild/moderate HIE and those with severe HIE. Results Among the 98 patients with HIE that received TH, 2 (2%) had mild HIE, 75 (77%) had moderate HIE and 21 (21%) had severe HIE on admission. Mortality rate was 10% (10/98) and median length of stay was 12 days [IQR 10-16]. Total mean cost per infant using the CNN algorithm was $32,727 (SD $23,751 and correlated highly to the CPSS mean $28.373(SD $28.989) (r=0.93, p&amp;lt;0.01). There was no significant difference in mean total costs estimated between the algorithms ($1051, 95% CI $-1073, $3174). There was a strong correlation between cost estimates using the CNN algorithm and CPSS in nursing, physician, transfusion and indirect costs (r range 0.94-0.99) (Figure 1). Mean daily costs per infant with mild/moderate HIE ($1579, SD 808) were lower compared to infants with severe HIE ($2069, SD 1518). In both groups, daily costs were higher in the first days of hospitalization and slightly decreased over time (Figure 2). Conclusion The CNN algorithm accurately predicts hospital stay costs for infants diagnosed with HIE and received TH in our centre. Severity of encephalopathy and severity of illness are associated with higher hospital costs.

Application Analysis of Accompanying Nursing Mode Combined with Health Education in Hyperbaric Oxygen Therapy for Infants with Hypoxic Ischemic Encephalopathy

To study application effect of accompanying nursing mode and health education on infants with hypoxic ischemic encephalopathy (HIE) treated with hyperbaric oxygen therapy (HBOT) via pure oxygen chamber. 124 cases of HIE infants treated with pure oxygen chamberHBOT admitted to our department (December 2018-December 2019) were chosen as the research samples, and split into experimental group and control group according to the order of admission, with 62 cases in each group. The control group received routine nursing while and the experimental group received accompanying nursing mode combined with health education to compare the mental development index (MDI), psychomotor development index (PDI), height, weight, neurological sequelae, efficacy and family members’ satisfaction with HBOT between the two groups. After nursing, MDI and PDI in experimental group were obviously higher compared with control group (P&lt;0.001);After nursing, the height and weight indexes in experimental group were obviously higher compared with control group (P&lt;0.05);After nursing, the total incidence of neurological sequelae in experimental group (3.2%) was obviously lower compared with control group (P&lt;0.05);After nursing, the total number of effective infants in experimental group was obviously higher compared with control group (P&lt;0.05);After nursing, the number of family members satisfied with HBOT in experimental group was obviously higher compared with control group (P&lt;0.05).The accompanying nursing mode combined with health education can greatly improve clinical indicators of HIE infants treated with pure oxygen chamber HBOT, promote their physical and mental development, and then improve the satisfaction of the family members with pure oxygen chamber HBOT, which should be promoted and applied in clinical practice as a high-quality nursing mode.

Temporal Trends in the Severity and Mortality of Neonatal Hypoxic-Ischemic Encephalopathy in the Era of Hypothermia

Introduction: There is a paucity of studies examining temporal trends in the incidence and mortality of moderate-to-severe hypoxic-ischemic encephalopathy (HIE) during the last decade of therapeutic hypothermia (TH). Methods: Multicenter cross-sectional study of all infants ≥35 weeks gestational age diagnosed with moderate-to-severe HIE within 6 h of birth in an extensive region of Spain between 2011 and 2019, in order to detect trend changes over time in the (1) annual incidence, (2) severity of neurological and systemic organ involvement, and (3) neonatal death from HIE. Results: Annual incidence rate of moderate-to-severe HIE was 0.84 (95% confidence interval [CI] 0.7–0.97) per 1,000 births, without trend changes over time (p = 0.8), although the proportion of severe HIE infants showed an average annual decline of 0.86 points (95% CI 0.75–0.98). There were 102 (70%) infants diagnosed with moderate HIE and 44 (30%) with severe HIE. TH was offered to 139/146 (95%) infants. Infants with clinical and/or electrical seizures showed a decreasing trend from 56 to 28% (p = 0.006). Mortality showed a nonstatistically significant decline (p = 0.4), and the severity of systemic damage showed no changes (p = 0.3). Obstetric characteristics remained unchanged, while higher perinatal pH values (p = 0.03) and Apgar scores (p = 0.05), and less need for resuscitation (p = 0.07), were found over time. Conclusion: The annual incidence of moderate-to-severe HIE has stabilized at around 1 per 1,000 births, with a temporal trend toward a decrease in severe HIE infants and a slight decline of mortality. No association was found between temporal trends and changes in perinatal/obstetric characteristics over time.

Association of Hypoxic Ischemic Encephalopathy With Hyponatremia In Term Infants Within First 24 Hours of Life

Background: Electrolytes disturbances observed in hypoxic ischemic encephalopathy can further complicate the already asphyxiated babies Serum sodium is one of the most important electrolytes associated with neuronal activity, routinely serum sodium is added after 24 hour of life in maintenance fluid of neonates but we will monitor the changes in our suspected cases earlier so that early intervention should be done to reduce the perinatal mortality and its fatal outcomes. Aim: To determine the association of hyponatremia with hypoxic ischemic encephalopathy in term infants during first 24 hours of life. Methods: Case control study was carried out at Department of Pediatrics, Aziz Bhatti Shaheed Teaching Hospital Gujrat from12th Feb 2018 to 12th Feb 2019. 134 cases and 134 controls were included in the study. Full term babies (&gt;37 weeks) of either gender was included for both cases and controls. Cases were hypoxic ischemic encephalopathy infants who has history of delayed cry at birth of &gt;5 minutes, respiratory distress and moaning. Hyponatremia was labelled if serum sodium levels are below 130 mmol/lit. Matched controls i.e. healthy neonates from same setting were selected for the study. The serum sodium levels were compared between cases and controls. Results: Serum sodium was unequally distributed among cases &amp; controls (Median±IQR 136±5, 139±8, P value using Mann Whitney U test= 0.01). Hyponatremia was also unequally distributed among cases &amp; controls (3.4% vs 0.4%, P value using Fischer exact test = 0.01). Logistic regression analysis using STEP wise analysis proved that the association found regarding hyponatremia/ serum sodium with hypoxic ischemic encephalopathy is not significant after adjusting for weight and gender of the infant. The distribution of birth weight and gender among cases and controls was similar (P value &gt; 0.05). Conclusion: It is concluded that hyponatremia is not associated with hypoxic ischemic encephalopathy in term infants during first 24 hours of life. Keywords: Hypoxic ischemic encephalopathy, Hyponatremia, Serum sodium, Perinatal asphyxia

NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

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

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.

Clinical seizures and unfavorable brain MRI patterns in neonates with hypoxic ischemic encephalopathy.

The aim was to examine whether clinical seizures and amplitude-integrated electroencephalogram (aEEG) patterns in infants with hypoxic ischemic encephalopathy (HIE) can predict the extent of brain injury on magnetic resonance images (MRI) and the long-term neurodevelopmental outcomes at 18∼24 months of age.HIE infants who underwent therapeutic hypothermia (TH) between June 2014 and March 2017 were included in this study. Infants with clinical seizure were analyzed for aEEG patterns and the extent of brain injury on MRI findings. Clinical seizure, aEEG, and brain MRI were assessed and compared with neurodevelopmental outcomes at 18∼24 months of age.Among the 97 HIE infants enrolled in this study with brain MRI scans, 78 (73.1%) TH-treated HIE infants exhibited clinical seizures. More abnormalities on a EEGs and more significant use of first and second antiepileptic drugs (AEDs) were significantly higher in the clinical-seizure group with longer hospitalized days. At a corrected 18 to 24 months of age, HIE infants in the clinical-seizure group with more extension of injury lesions on diffusion-weighted MRI scans exhibited significantly more delayed neurodevelopment. A risk factor analysis indicated that male infants who stayed in the hospital for more than 11 days were at a higher risk of having clinical seizures. The lesion size in MRI greater than 37 pixels was a risk factor with an 81.8% accuracy.Seizures in HIE infants may predict abnormal brain MRI scans and abnormal neurodevelopment at 18 to 24 months of age.

The effects of monotherapy with erythropoietin in neonatal hypoxic-ischemic encephalopathy on neurobehavioral development: a systematic review and meta-analysis.

Previous systematic review has shown the safety and efficiency of EPO (erythropoietin) for neonatal hypoxic-ischemic encephalopathy (HIE). To date, the evidence is limited that EPO is beneficial to therapeutic hypothermia as an adjuvant. There has not a brief discussion about the neuroprotection effects of EPO without hypothermia. To evaluate the long-term prognosis of HIE treated with EPO alone, we carried out this study that can be a supplement to the previous meta-analysis. 7 databases (including PubMed, EMBASE, Cochrane, CKNI, CBM, WanFang, and VIP) and the ClinicalTrials.gov were retrieved from inception to 1 March 2020. The inclusion criteria were RCTs with EPO treatment without hypothermia. The outcomes were tested by using the Bayley Scales of Infant Development (BSID), including the Bayley Mental Development Index Score (MDI) and the Bayley Psychomotor Development Index Score (PDI). This meta-analysis was done to compare the Risk Ratio (RR) for the scores of BSID less than 70 after over 6 months of follow-up. 11 RCTs (1099 newborns) were included, excluding deaths and lost visits, and 917 patients finally were performed the statistical analysis. In neonatal HIE infants, investigation results showed a lower risk of cognitive impairment and psychomotor disability with EPO monotherapy. The pooled event rates of MDI <70 saw a reduction of 36% (95% CI 24%-54%) compared to the control group. There was a decrease of 37% (95% CI 24%-56%) of Psychomotor abnormal (PDI <70) in the EPO group. EPO administration alone could improve the scores of mental and psychomotor in neonates with HIE. However, the level of evidence is low to moderate for the insufficient sample size, so large-scale, multicenter clinical trials are still needed.

Hearing Impairment in Infants with Hypoxic Ischemic Encephalopathy Treated with Hypothermia.

Therapeutic hypothermia acts as the standard of care for infants with moderate to severe hypoxic ischemic encephalopathy (HIE). A proportion of neonates who undergo hypothermia due to HIE have shown to develop various degrees of hearing impairment. Analyzing and identifying infants at high risk of developing hearing difficulties is fundamental for early intervention of such auditory complications. The aim was to assess clinical factors in the development of hearing impairment following therapeutic hypothermia in HIE infants. A retrospective analysis was performed on infants hospitalized in our neonatology department in Poznan University of Medical Sciences, Poland. All infants experienced moderate to severe HIE, and were treated with therapeutic hypothermia. Risk factors for hearing impairment were identified in all infants included in the study. Clinical data during hospital stay and follow-up hearing status were analyzed. A total of 87 HIE infants were included in the study. Seventy-six infants (40 male and 36 female) had otoacoustic emission (OAE) examination following birth, of which 14 (18.4%) demonstrated abnormal (positive) results. Infants with abnormal OAE results had significantly lower blood pH (6.86 ± 0.16, p = 0.001) and base excess (BE) (-22.46 ± 2.59, p = 0.006). Of the 49 infants who returned for follow-up assessment, 4 (8.2%) were diagnosed with sensorineural bilateral hearing impairment (1 infant, mild [<40 dB], 2 moderate [41-70 dB], and 1 profound [>90 dB]). The biochemical analysis following birth revealed significantly lower umbilical BE levels (-23.90 ± 4.99, p = 0.041) and higher lactate levels (160.67 ± 4.93, p = 0.019) in the infants with eventual sensorineural hearing deficit. Infants with moderate or severe HIE are at risk of delayed onset hearing loss. Diligent efforts to monitor auditory status are required, even if early screening results for hearing are insignificant. Exploring biochemical parameters, such as lactate, BE, and blood pH, can prove beneficial in identifying HIE infants at risk of developing a hearing impairment.