Severe Neonatal Hypoxic-ischemic Encephalopathy Research Articles

A biochemical feedback signal for hypothermia treatment for neonatal hypoxic-ischemic encephalopathy: focusing on central nervous system proteins in biofluids.

Hypothermia has been widely used to treat moderate to severe neonatal hypoxic-ischemic encephalopathy (HIE), yet evaluating the effects of hypothermia relies on clinical neurology, neuroimaging, amplitude-integrated electroencephalography, and follow-up data on patient outcomes. Biomarkers of brain injury have been considered for estimating the effects of hypothermia. Proteins specific to the central nervous system (CNS) are components of nervous tissue, and once the CNS is damaged, these proteins are released into biofluids (cerebrospinal fluid, blood, urine, tears, saliva), and they can be used as markers of brain damage. Clinical reports have shown that CNS-specific marker proteins (CNSPs) were early expressed in biofluids after brain damage and formed unique biochemical profiles. As a result, these markers may serve as an indicator for screening brain injury in infants, monitoring disease progression, identifying damage region of brain, and assessing the efficacy of neuroprotective measures. In clinical work, we have found that there are few reports on using CNSPs as biological signals in hypothermia for neonatal HIE. The aim of this article is to review the classification, origin, biochemical composition, and physiological function of CNSPs with changes in their expression levels after hypothermia for neonatal HIE. Hopefully, this review will improve the awareness of CNSPs among pediatricians, and encourage future studies exploring the mechanisms behind the effects of hypothermia on these CNSPs, in order to reduce the adverse outcome of neonatal HIE.

Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy.

Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH. This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15). Data quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (β (SE)=4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10moL/dl×mm2/s, P=0.009 and P=0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. Point of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE. This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).

Defining Longer-Term Outcomes in an Ovine Model of Moderate Perinatal Hypoxia-Ischemia

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of neonatal morbidity and mortality worldwide. Approximately 1 million infants born with HIE each year survive with cerebral palsy and/or serious cognitive disabilities. While infants born with mild and severe HIE frequently result in predictable outcomes, infants born with moderate HIE exhibit variable outcomes that are highly unpredictable. Here, we describe an umbilical cord occlusion (UCO) model of moderate HIE with a 6-day follow-up. Near-term lambs (n = 27) were resuscitated after the induction of 5 min of asystole. Following recovery, lambs were assessed to define neurodevelopmental outcomes. At the end of this period, lambs were euthanized, and brains were harvested for histological analysis. Compared with prior models that typically follow lambs for 3 days, the observation of neurobehavioral outcomes for 6 days enabled identification of animals that recover significant neurological function. Approximately 35% of lambs exhibited severe motor deficits throughout the entirety of the 6-day course and, in the most severely affected lambs, developed spastic diparesis similar to that observed in infants who survive severe neonatal HIE (severe, UCOs). Importantly, and similar to outcomes in human neonates, while initially developing significant acidosis and encephalopathy, the remainder of the lambs in this model recovered normal motor activity and exhibited normal neurodevelopmental outcomes by 6 days of life (improved, UCOi). The UCOs group exhibited gliosis and inflammation in both white and gray matters, oligodendrocyte loss, neuronal loss, and cellular death in the hippocampus and cingulate cortex. While the UCOi group exhibited more cellular death and gliosis in the parasagittal cortex, they demonstrated more preserved white matter markers, along with reduced markers of inflammation and lower cellular death and neuronal loss in Ca3 of the hippocampus compared with UCOs lambs. Our large animal model of moderate HIE with prolonged follow-up will help further define pathophysiologic drivers of brain injury while enabling identification of predictive biomarkers that correlate with disease outcomes and ultimately help support development of therapeutic approaches to this challenging clinical scenario.

Implementation of a revised classification for intrapartum fetal heart rate monitoring and association to birth outcome: Anational cohort study.

A revised intrapartum cardiotocography (CTG) classification was introduced in Sweden in 2017. The aims of the revision were to adapt to the international guideline published in 2015 and to adjust the classification of CTG patterns to current evidence regarding intrapartum fetal physiology. This study aimed to investigate adverse neonatal outcomes before and after implementation of the revised CTG classification. A before-and-after design was used. Cohort I (n=160210) included births from June 1, 2014 through May 31, 2016 using the former CTG classification, and cohort II (n=166558) included births from June 1, 2018 through May 31, 2020 with the revised classification. Data were collected from the Swedish Pregnancy and Neonatal Registers. The primary outcome was moderate to severe neonatal hypoxic ischemic encephalopathy (HIE 2-3). Secondary outcomes were birth acidemia (umbilical artery pH <7.05 and base excess < -12mmol/L or pH <7.00), A-criteria for neonatal hypothermia treatment, 5-min Apgar scores <4 and <7, neonatal seizures, meconium aspiration, neonatal mortality and delivery mode. Logistic regression was used (period II vs period I), and results are presented as adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs). There were no statistically significant differences in HIE 2-3 (aOR 1.27; 95% CI 0.97-1.66), proportion of neonates meeting A-criteria for hypothermia treatment (aOR 0.96; 95% CI 0.89-1.04) or neonatal mortality (aOR 0.68; 95% CI 0.39-1.18) between the cohorts. Birth acidemia (aOR 1.36; 95% CI 1.25-1.48), 5-min Apgar scores <7 (aOR 1.27; 95% CI 1.18-1.36) and <4 (aOR 1.40; 95% CI 1.17-1.66) occurred more often in cohort II. The absolute risk difference for HIE 2-3 was 0.02% (95% CI 0.00-0.04). Operative delivery (vacuum or cesarean) rates were lower in cohort II (aOR 0.82; 95% CI 0.80-0.85 and aOR 0.94; 95% CI 0.91-0.97, respectively). Although not statistically significant, a small increase in the incidence of HIE 2-3 after implementation of the revised CTG classification cannot be excluded. Operative deliveries were fewer but incidences of acidemia and low Apgar scores were higher in the latter cohort. This warrants further in-depth analyses before a full re-evaluation of the revised classification can be made.

Application of apparent diffusion coefficient histogram in moderate to severe neonatal hypoxic-ischemic encephalopathy

Objective: To investigate the diagnostic value of apparent diffusion coefficient (ADC) histogram in quantifying moderate to severe neonatal hypoxic-ischemic encephalopathy (HIE). Methods: A total of 49 children with moderate to severe HIE admitted to the Children's Hospital Affiliated to Nanjing Medical University from July 2015 to September 2018 were retrospectively analyzed. Cranial magnetic resonance imaging (MRI) data of 31 full-term neonates without neurological symptoms and signs who visited the hospital during the same period were recruited as the control group. ImgJ software was used to delineate the whole brain area at the thalamus/basal ganglia level as the area of interest, and MRIcron software was used to obtain ADC histogram parameters. The differences of ADC histogram parameters between HIE group and control group were compared. The correlation between ADC histogram parameters and neonatal neurobehavioral neurological assessment (NBNA) in HIE group was analyzed. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficiency of each parameter. Results: The mean value, minimum value, maximum value, mode-value, variance, heterogeneity and 10%-90% ADC values of HIE group were all greater than those of the control group(634±65,310±36,1 683±18,711±87,66 928±921,5 907±204,477±50,513±53,542±56,568±59,591±61,625±92,661±97,709±105,811±119),the differences were statistically significant(all P<0.05), while mode-count of HIE group was smaller than that of the control group(272±22 to 395±83), and the difference was statistically significant (t=2.996,P<0.05). All the above parameters with statistical differences were correlated with NBNA score, among which mode-count was negatively correlated with NBNA score(r=-0.369,P<0.05), and the rest were positively correlated(all P<0.05). The area under the ROC curve (AUC) of variance had the highest diagnostic efficiency (0.881), followed by 90% ADC value and ADC maximum value. Conclusion: ADC histogram is helpful for the diagnosis of HIE, objectively and quantitatively reflecting the diffusion information of brain, and assessing the severity of HIE.

Hypoxia-inducible factor: role in cell survival in superoxide dismutase overexpressing mice after neonatal hypoxia-ischemia.

BackgroundSixty percent of infants with severe neonatal hypoxic-ischemic encephalopathy die, while most survivors have permanent disabilities. Treatment for neonatal hypoxic-ischemic encephalopathy is limited to therapeutic hypothermia, but it does not offer complete protection. Here, we investigated whether hypoxia-inducible factor (HIF) promotes cell survival and suggested neuroprotective strategies.PurposeHIF-1α deficient mice have increased brain injury after neonatal hypoxia-ischemia (HI), and the role of HIF-2α in HI is not well characterized. Copper-zinc superoxide dismutase (SOD)1 overexpression is not beneficial in neonatal HI. The expression of HIF-1α and HIF-2α was measured in SOD1 overexpressing mice and compared to wild-type littermates to see if alteration in expression explains this lack of benefit.MethodsOn postnatal day 9, C57Bl/6 mice were subjected to HI, and protein expression was measured by western blotting in the ipsilateral cortex of wild-type and SOD1 overexpressing mice to quantify HIF-1α and HIF-2α. Spectrin expression was also measured to characterize the mechanism of cell death.ResultsHIF-1α protein expression did not significantly change after HI injury in the SOD1 overexpressing or wild-type mouse cortex. However, HIF-2α protein expression increased 30 minutes after HI injury in the wild-type and SOD1 overexpressing mouse cortex and decreased to baseline value at 24 hours after HI injury. Spectrin 145/150 expression did not significantly change after HI injury in the SOD1 overexpressing or wild-type mouse cortex. However, spectrin 120 expression increased in both wild-type and SOD1 overexpressing mouse at 4 hours after HI, which decreased by 24 hours, indicating a greater role of apoptotic cell death.ConclusionHIF-1α and HIF-2α may promote cell survival in neonatal HI in a cell-specific and regional fashion. Our findings suggest that early HIF-2α upregulation precedes apoptotic cell death and limits necrotic cell death. However, the influence of SOD was not clarified; it remains an intriguing factor in neonatal HI.

DYNAMICS FOR SERUM BIOMARKERS OF BRAIN DAMAGE IN TERM INFANTS DURING ACUTE PERIOD OF HYPOXIC-ISCHEMIC ENCEPHALOPATHY

To date, it remains unclear whether serum levels of the neuron-specific enolase (NSE) andthe S-100 protein definitely correspond tothe severity and possible outcomes of hypoxicischemic encephalopathy (HIE), as well as their predictable values regarding to thepotential development of such an unfavorableresult of HIEtreatment as cerebralleukomalacia.Objective to evaluatethe dynamics of such serum biomarkersas neuron-specific enolase(NSE) and protein S-100 in full-term newborns during the acute period of HIE and findout their possible correlation with the development of cerebral leukomalacia.Materials and methods. A prospective, single-center cohort study was performed in 205full-term infants,weretreated in the neonatal intensive care unit due to hypoxic-ischemicencephalopathy in 2012-2017.All the babieswere stratifiedby the diagnosis of cerebralleukomalacia, which complicated the treatment of moderate to severe neonatal hypoxicischemic encephalopathy. Serum concentrations of neuron-specific enolase (NSE) andprotein S-100 were determined on 1st, 3rd and 5th days of treatment both in total cohortand in subgroups with and without development of leukomalacia.Results. Serum concentrations of both biomarkers significantly exceeded the normalvalues in whole cohort during all days of the research, but the dynamics of their declinediffered from each other. Basingon multivariate analysis of variance ANOVA, a significantcorrelation of the S-100 protein level on the 1st day of treatment with the possibledevelopment of cerebral leukomalacia was determined (p=0.024), but we did not revealed the same to the neuron-specific enolase (p=0.656), despite its dynamicssignificantly changed at all stages of the study.Conclusions. Evaluationfor serum concentrations of such biomarkers of brain damage asprotein S-100 and neuron-specific enolase in the acute period of hypoxic-ischemicencephalopathy in full-term newborns has a significant diagnostic and prognostic valueand correlates with the severity and outcomes of HIE.

Hospital-related, maternal, and fetal risk factors for neonatal asphyxia and moderate or severe hypoxic-ischemic encephalopathy: a retrospective cohort study

Aim A previous large US study had documented an increased risk of asphyxia in small volume and rural hospitals. Our objective was to evaluate this in all hospitals in Alberta, a Canadian province. Methods Retrospective cohort study of all singleton births ≥ 35-week gestation, in Alberta, from 2002–16 recorded in a perinatal database. Asphyxia was defined as intrapartum stillbirth or neonatal death from asphyxia or Neonatal Intensive Care Unit admission and at least two of the following: a. Apgar score of ≤ 5 at 10 minutes; b. mechanical ventilation or chest compressions for resuscitation within 10 minutes; c. cord pH < 7.00 (venous or arterial), or arterial base excess ≥ 12 at birth. Urban hospitals were defined as those serving a population of ≥ 50 000. Hospital volume was categorized by the following: urban: < 1200, 1200–2399, 2400–3600, > 3600 annual births and Rural: < 50, 50–599, 600–1699 annual births. Data on moderate–severe neonatal hypoxic-ischemic encephalopathy was also obtained from two provincial asphyxia databases for 2010–2016. Results The overall rate of neonatal asphyxia was 2.28 per 1000 births for the study period and was 2.5/1000 in the urban hospitals and 1.35/1000 in the rural hospitals, OR: 1.86 95% CI (1.58, 2.19). The rate of moderate or severe neonatal hypoxic-ischemic encephalopathy was 0.9/1000 and was not associated with urban hospital birth; OR: 1.12 95%CI (0.82, 1.53) hospital volume was also not associated with asphyxia or moderate or severe neonatal hypoxic-ischemic encephalopathy. Conclusions This study observed similar rates of asphyxia and moderate or severe neonatal hypoxic-ischemic encephalopathy for rural and urban hospitals in Alberta and no association with hospital volume.

Early infantile epileptic encephalopathy type 4: clinical, neurophysiological and therapeutic aspects

Objective . Study the clinical and neurophysiological evolution of early infantile epileptic encephalopathy type 4 (EIEE4) caused by a STXBP1 gene mutation. Material and methods. During 2016-2019, we conducted dynamic observation and treatment of a girl with EIEE4 combined with a mutation in the STXBP1 gene. DNA sequencing was performed using the Hereditary epilepsies panel (Next Generation Sequencing on the platform of Illumina HiSeq 2500, USA). Dynamic video-EEG monitoring was performed with an “Encephalan-Video RM-19/26 (Medicom MTD“, Russia). Results. In this 3.5 y.o. patient with infantile epileptic encephalopathy, a heterozygous autosomal dominant de novo mutation in the STXBP1 gene was found. This mutation (not described previously) is located in chromosome 9, specifically, in the 20th exon with genome coordinates Chr9:130453 (C.*96T>A). This child suffered from severe neonatal hypoxic-ischemic encephalopathy, which led to spastic cerebral palsy. In addition, she developed seizures as early as at the age of 6 month; the seizures (flexor tonic spasms) were paralleled with EEG changes similar to the Mar-kand-Blume-Ohtahara syndrome, namely, multiple independent spike-wave foci in combination with the partial attenuation pattern (kind of the burst-suppression pattern). Valproate monotherapy had little effect, and hormonal treatment caused a temporary improvement. Permanent clinical remission with no seizures was achieved by including leveti-racetam in the therapeutic combination. A number of studies demonstrated a high efficacy of levetiracetam in cases of STXBP1 gene mutations. At the age of 2,5years, the girl demonstrated changes in her EEG records toward the continuous spike-wave during sleep (CSWS) pattern with the morphology of benign epileptiform discharges of childhood (BEDC). Conclusions. In spite of the aggravated perinatal anamnesis, children with epileptic encephalopathy need genetic examination using the Next Generation Sequencing (NGS) methods (such as Hereditary epilepsies panel), combined with full exome sequencing. Such genetic examinations are helpful for establishing the exact etiology of epilepsy and developing a personalized approach to antiepileptic therapy.

Thrombin Preconditioning Enhances Therapeutic Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells in Severe Neonatal Hypoxic Ischemic Encephalopathy.

We investigated whether thrombin preconditioning of human Wharton’s jelly–derived mesenchymal stem cells (MSCs) improves paracrine potency and thus the therapeutic efficacy of naïve MSCs against severe hypoxic ischemic encephalopathy (HIE). Thrombin preconditioning significantly enhances the neuroprotective anti-oxidative, anti-apoptotic, and anti-cytotoxic effects of naïve MSCs against oxygen–glucose deprivation (OGD) of cortical neurons in vitro. Severe HIE was induced in vivo using unilateral carotid artery ligation and hypoxia for 2 h and confirmed using brain magnetic resonance imaging (MRI) involving >40% of ipsilateral hemisphere at postnatal day (P) 7 in newborn rats. Delayed intraventricular transplantation of 1 × 105 thrombin preconditioned but not naïve MSCs at 24 h after hypothermia significantly enhanced observed anti-inflammatory, anti-astroglial, and anti-apoptotic effects and the ensuing brain infarction; behavioral tests, such as cylinder rearing and negative geotaxis tests, were conducted at P42. In summary, thrombin preconditioning of human Wharton’s jelly-derived MSCs significantly boosted the neuroprotective effects of naïve MSCs against OGD in vitro by enhancing their anti-oxidative, anti-apoptotic, and anti-cytotoxic effects, and significantly attenuated the severe HIE-induced brain infarction and improved behavioral function tests in vivo by maximizing their paracrine anti-inflammatory, anti-astroglial, and anti-apoptotic effects.

Efficacy and safety of selective brain hypothermia therapy on neonatal hypoxic-ischemic encephalopathy

To evaluate the efficacy and safety of selective brain hypothermia (SBH) in the treatment of neonates with moderate or severe neonatal hypoxic-ischemic encephalopathy (HIE), and the effect of SBH treatment on serum levels of neuron-specific enolase (NSE) and central nervous specific protein S100. A prospective randomized controlled trial was conducted. From January 2015 to June 2017, 42 children with moderate to severe HIE in the neonatal intensive care unit (NICU) of the First Affiliated Hospital of Bengbu Medical College were enrolled, and they were randomly divided into SBH treatment group and routine treatment group after obtaining the consent of the guardian of the children. The children in routine treatment group were given the traditional symptomatic supportive treatment, supplemented by drugs to promote nerve cell growth. On the basis of traditional treatment, the children in the SBH treatment group were given SBH treatment within 6 hours after birth. The nasopharyngeal temperature was maintained at 33.0-34.5 centigrade and the rectal temperature was maintained at 34.5-35.0 centigrade. The general clinical data of the two groups including gender, gestational age, birth weight, age, 5-minute neonatal asphyxia score (Apgar score), score for neonatal acute physiology perinatal extension version II (SNAPPE II) were collected. The primary outcomes were hospitalized death, severe disability at 15 months of age, neonatal behavioral neurological assessment (NBNA) score at 28 days of age, and Bayley scales of infant development (BSID) score [including mental development index (MDI) score and psychomotor development index (PDI) score] at 15 months of age at follow-up. The secondary outcomes were serum levels of NSE and S100 protein. The occurrences of adverse events in the two groups were recorded. Among 42 HIE children, 1 child of severe congenital malformation and 1 child of platelet count (PLT) < 50×109/L were excluded, and 40 children were enrolled in the study group. During the follow-up period, 2 children of SBH treatment group and 2 children of routine treatment group were lost or the outcome was unknown. Finally, 18 children of each group were enrolled in the analysis. There was no significant difference in the baseline data of gender, gestational age, birth weight, age, 5-minure Apgar score or SNAPPE II score between the two groups, indicating that the baseline data of the two groups were balanced and comparable. The incidence of severe disability in the SBH treatment group was significantly lower than that in the routine treatment group [5.6% (1/18) vs. 44.4% (8/18), P < 0.05]. There was 1 child death in the routine treatment group and no death in the SBH treatment group. Compared with the routine treatment group, the 28-day NBNA score of the SBH treatment group was increased by 2.9 [95% confidence interval (95%CI) = 1.0-4.8], BSID score at 15 months of age was improved significantly, MDI score was increased by 11.8 (95%CI = 4.3-19.3), and PDI score was increased by 12.4 (95%CI = 2.5-22.3), with significant differences between the two groups (all P < 0.05). After 3 days of treatment, the serum NSE and S100 protein levels in both groups were significantly decreased as compared with those before treatment [NSE (μg/L): 30.15±15.18 vs. 31.32±14.75, S100 (ng/L): 387.5 (273.3, 573.0) vs. 890.0 (590.5, 1 162.5) in routine treatment group; NSE (μg/L): 29.09±16.22 vs. 32.25±15.43, S100 (ng/L): 402.5 (302.2, 580.5) vs. 842.0 (462.3, 1 200.5) in SBH treatment group, all P < 0.05]. There was no significant difference in serum NSE or S100 protein level between the two groups (all P > 0.05). There was no serious adverse event such as arrhythmia, large vein thrombosis or irreducible hypotension in both groups, and there was no significant difference in the incidence of general adverse events such as sinus bradycardia, scleredema, blood glucose disorder, or systemic infection between the two groups [16.7% (3/18) vs. 11.1% (2/18), 5.6% (1/18) vs. 5.6% (1/18), 22.2% (4/18) vs. 11.1% (2/18), 5.6% (1/18) vs. 5.6% (1/18), all P > 0.05]. SBH treatment could significantly increase the NBNA score at 28 days of birth and BSID score at 15 months of age, reduce the incidence of severe disability in moderate and severe HIE children, but it was not be proved that SBH could reduce the mortality. Compared with routine treatment, SBH treatment had no significant superiority on improving the levels of serum NSE and S100 protein, suggesting that SBH could not protect the brain by inhibiting the apoptosis of nerve cells and promoting the repair of nerve cells.

Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy

Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.

Antepartum risk factors for moderate to severe neonatal hypoxic ischemic encephalopathy: a Swedish national cohort study.

Our aim was to identify antepartum risk factors for neonatal hypoxic ischemic encephalopathy, with a focus on maternal body mass index and height. National population-based cohort study of 692 428 live-born infants ≥36 gestational weeks in Sweden, 2009-2015. Data from the Swedish Medical Birth Register and the Swedish Neonatal Quality Register were linked. Short maternal stature was defined as ≤155 cm, and overweight as body mass index ≥25 kg/m2 . Therapeutic hypothermia served as surrogate marker of moderate to severe hypoxic ischemic encephalopathy. Associations between maternal and infant characteristics and hypoxic ischemic encephalopathy were calculated with logistic regression analyses, and risks were presented as odds ratios with 95% confidence intervals. Moderate to severe hypoxic ischemic encephalopathy occurred in 0.67/1000 infants. Nulliparity, previous cesarean delivery, short stature, overweight, gestational age, occiput posterior presentation and birthweight were all independently associated with hypoxic ischemic encephalopathy. The risk of hypoxic ischemic encephalopathy increased with decreasing maternal height and increasing body mass index. Compared with non-short women (≥156 cm) with normal weight (body mass index <25 kg/m2 ), those with both short stature and overweight had increased risk of hypoxic ischemic encephalopathy (odds ratio 3.66; 95% confidence intervals 2.41-5.55). Among parous women with both short stature and overweight, the risk was almost sixfold (odds ratio 5.74; 95% confidence intervals 3.41-9.66). Antepartum risk factors for moderate to severe hypoxic ischemic encephalopathy included nulliparity, previous cesarean delivery, short stature, overweight, gestational age, occiput posterior presentation and birthweight. The combination of maternal short stature and overweight was associated with a more than threefold risk of subsequent hypoxic ischemic encephalopathy.

Therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy is associated with short-term reduction of seizures after discharge from the neonatal intensive care unit.

Therapeutic hypothermia for the treatment of moderate to severe neonatal hypoxic ischemic encephalopathy has been shown to reduce death and disability, but the effects on seizures after discharge from the Neonatal ICU are not known. A retrospective cohort study was conducted involving 56 neonates admitted to the Neonatal ICU at Children's Hospital of Orange County, CA from January 1, 2007 to September 1, 2013 with hypoxic ischemic encephalopathy who met criteria for selective brain cooling. Fifteen patients received supportive care. Forty-one patients received cooling, of whom 25 were included for analysis. Sixteen patients from the hypothermia group and 12 from the no hypothermia group developed clinical seizures while inpatient. Up to 6months, four patients (16%) had continued seizures in the therapeutic hypothermia group compared to eight (53%) patients who did not receive hypothermia. Our study shows an association between therapeutic hypothermia and reduced seizures after discharge from the neonatal intensive care unit. The short duration of follow-up, 6months, is a limitation of this study. Another limitation is its observational nature, where reasons for treatment selection and exclusions are unmeasurable confounding factors. Further studies are needed to determine long-term effects.

Hypothermia reduces seizure burden and improves neurological outcome in severe hypoxic–ischemic encephalopathy: an observational study

To evaluate the antiepileptic effect of hypothermia and its association with neurological outcome in infants with moderate and severe hypoxic-ischemic encephalopathy (HIE). We compared polygraphic electroencephalography monitoring and outcome data in 39 cooled and 33 non-cooled term newborn infants, born between January 2005 and March 2013, and hospitalized because of signs of asphyxia and moderate to severe HIE. Cooled newborn infants had fewer seizures (14/39 vs 20/33 p=0.036) and status epilepticus (7/39 vs 13/33, p=0.043), a lower mean duration of seizures (18mins vs 133mins, p=0.026), fewer administered antiepileptic drugs (median 0 vs 1, p=0.045), and more commonly a good outcome at 24 months (normal/mild motor impairment in 32/39 vs 16/33, p=0.003). Seizure burden (accumulated duration of seizures over a defined period) in cooled patients with both moderate (0.0 vs 0.1; p=0.045) and severe HIE (0.3 vs 4.9; p=0.018) was lower than in non-cooled patients. Compared with non-cooled patients, a good outcome was more common in cooled newborn infants with severe HIE (p=0.003). Hypothermia has an antiepileptic effect in both moderate and severe neonatal HIE. The lower seizure burden in cooled newborn infants with severe HIE is more commonly associated with normal outcome at 24 months.

Neonatal Hypoxic Ischemic Encephalopathy: A Case Study

Hypoxic ischemic encephalopathy (HIE) of the neonate is a devastating consequence of a spectrum of perinatal complications. The etiology of HIE is multifactorial with the level of neurological injury influenced by both the degree of ischemic insult and the infant’s gestational age. Early diagnostic imaging provides healthcare providers with objective data following ischemic brain injury, however it is unclear which modality or combination of modalities may provide the best prognostic information. Diffusion-weighted MRI has become the diagnostic tool of choice in moderate to severe neonatal HIE with a high predictive value; however the utility of MRI alone in mild HIE remains unclear. This case review presents an infant with HIE with abnormalities in both early cranial ultrasound and EEG, yet with a post-cooling MRI without significant abnormality. This case suggests that in mild HIE, multiple imaging modalities may be a more accurate predictor for neurological outcomes than MRI alone.

Efficacy and safety of systemic mild hypothermia treatment for moderate or severe neonatal hypoxic-ischemic encephalopathy

Objective To explore the efficacy and safety of systemic mild hypothermia in management of neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). Methods A retrospective case-control study was conducted on 75 neonates with moderate or severe HIE, who were admitted to the Neonatal Intensive Care Unit of Teaching Hospital of Fujian Medical University (Quanzhou Children's Hospital) from January 1, 2011 to May 31, 2015. The 75 neonates were divided into two groups, the conventional treatment group (33 cases, control group) and the mild hypothermia treatment group (42 cases, hypothermia group). Sequential management protocol for all subjects was followed, including amplitude-integrated electroencephalogram (aEEG) before treatment, aEEG and brain MRI at one week after birth, neonatal behavioral neurological assessment (NBNA) on the 14th day after birth, and determination of mental and psychomotor development index with Bayley Scales of Infant and Toddler Developmental at 18 months old. Adverse reactions, serious disability cases and deaths during the study were also recorded. Two sample-t test and Chi-square test were as statistical methods. Results There were six death cases in the control group, but on one died in the hypothermia group. In the survivals, The maximum voltage and minimum voltage in the hypothermia group were higher at 7-day old than that before treatment [maximum voltage: (31.3±2.4) vs (18.1±2.2) μV; minimum voltage: (13.5±2.1) vs (6.1±1.5) μV, t=8.591 and 5.314, both P 0.05). Conclusions Systemic mild hypothermia treatment is effective in reducing mortality rate and major disability rate in neonates with moderate or severe HIE and improves the neuromotor development when babies grow up to 18-month-old. Key words: Hypoxia-ischemia,brain; Hypothermia, induced; Infant,newborn

Detecting brain injury in neonatal hypoxic ischemic encephalopathy: Closing the gap between experimental and clinical research

Moderate to severe neonatal hypoxic ischemic encephalopathy remains an important cause of infant death and childhood disability. Early and accurate diagnosis of encephalopathy is difficult but critical for timely intervention. Thus, we have utilized a clinically relevant large animal model of asphyxia in-utero, followed by immediate lamb delivery, resuscitation and clinical care over the next 72h for assessment of potential biomarkers of brain injury. In-utero asphyxia was induced in twelve near-term lambs and outcomes compared with seven controls. Asphyxia resulted in bradycardia (97±12beats/min), hypotension (12.1±1mm Hg) and metabolic acidosis (pH6.9±0.02; base-excess −13.8±0.8mmol/l). 72h following asphyxia, cerebrospinal concentrations of malondialdehyde and S100B were elevated 2-fold and 5-fold, respectively, in asphyxic lambs compared to control lambs. Magnetic resonance spectroscopy (MRS) at 72h showed a significant decrease in n-acetyl aspartate: choline ratio in asphyxia lambs compared to that observed at 12h (0.56±0.23 vs. 0.82±0.15, respectively); lactate:choline ratio was not changed over this time. Marked neuropathology was observed in asphyxia lambs with neuronal degeneration in the hippocampus, thalamus, striatum and cortex. Astrogliosis was observed in the hippocampus and thalamus. Early blood markers of metabolic state showed limited predictive value of histological damage at 72h. MRS outcomes at 72h showed a modest but significant correlation with histological evidence of neuronal brain injury (lactate:N-acetyl aspartate ratio in the thalamus r2=0.2, p<0.01). MRS at 72h was best able to detect established brain injury, but a combination of biomarkers over multiple phases of injury may be able to assess the evolution of neonatal brain injury.

The myocardial function during and after whole-body therapeutic hypothermia for hypoxic–ischemic encephalopathy, a cohort study

BackgroundTherapeutic hypothermia has become standard treatment for moderate and severe neonatal hypoxic–ischemic encephalopathy (HIE) to reduce cerebral morbidity and mortality. The effect on the heart is incompletely explored. AimTo assess the myocardial function during and after whole-body therapeutic hypothermia for HIE. Study designObservational cohort study. SubjectsForty-four infants with HIE cooled for 72hours were compared with 48 healthy term infants and 20 normothermic infants with HIE. Outcome measuresTissue Doppler deformation indices of myocardial function (peak systolic strain, peak systolic strain-rate, early diastole strain-rate and strain-rate in atrial systole) during (days 1 and 3) and after (day 4) therapeutic hypothermia. ResultsOn days one and three all indices in both HIE groups were lower than the corresponding indices in the healthy infants. The two HIE groups had similar indices, except peak systolic strain-rate on days 1 and 3 and strain-rate in atrial systole on day 1. All strain-rate indices improved from day 3 to 4 (after rewarming) in the cooled group and achieved similar values to those in healthy infants on day 3. All indices were higher in the cooling-group after rewarming than in the normothermic infants with HIE on day 3, except early diastolic strain-rate. ConclusionsInfants with HIE had similarly impaired myocardial function during days 1–3 whether normothermic or hypothermic. The myocardial function improved significantly at day 4 (after rewarming), approaching the day 3 levels in the healthy neonates.

Clinical observation of naloxone for the treatment of neonatal hypoxic-ischemic encephalopathy

Objective To explore effective treatment for moderate and severe neonatal hypoxic-ischemic encephalopathy(HIE).Methods 46 cases of moderate to severe HIE were randomly divided into two groups.Control group of 21 cases only accepted the HIE conventional treatment,treatment group,25 cases accepted the HIE conventional treatment and were also given brain protein hydrolyzate combined naloxone treatment,the efficacy of various clinical indicators of the two groups were compared.Results The remarkable effective rate and the total effective rate of the treatment group were significantly higher ( all P ＜ 0.01 ).Consciousness recovery time,recovery time of the original ability,convulsions,muscle tension,recovery time,sucking ability,recovery time,hospital days of treatment group were significantly lower than the control group( P ＜ 0.05 or P ＜ 0.01 ).Conclusion The effect of naloxone therapy for moderate to severe HIE is significant,and the therapy has high clinical value. Key words: Neonatal hypoxic-ischemia,brain; Naloxone; Brain protein hydrolyzate