Hypoxic-ischemic Encephalopathy In Term Infants Research Articles

Changes of Oxidative Stress-Related Gene Expression in an in vitro Model of Neonatal Hypoxic-Ischemic Encephalopathy

Background: We recently demonstrated that oxygen-glucose deprivation (OGD) and unconjugated bilirubin (UCB) can damage mature and immature organotypic hippocampal slices and induce an oxidative stress similar to what occurs in jaundiced term and preterm infants with hypoxic-ischemic encephalopathy (HIE). Objectives: To assess the effects of OGD and UCB on the expression of heme-oxygenase 1 (HO-1) and oxidative stress-related enzymes in an in vitro model of HIE. Methods: Mature and immature organotypic hippocampal slices were exposed to 30-min OGD and to 24 h UCB or UCB plus human serum albumin (HSA). The expression of HO-1, superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase (GPX), and nuclear factor erythroid-related factor 2 were analyzed by real-time PCR. Results: In mature slices, OGD did not affect the expression of HO-1 and oxidative stress-induced enzymes. The addition of UCB was associated with the upregulation of HO-1 and Nrf2 that is abolished by the presence of equimolar amount of HSA. In immature slices, OGD induced the downregulation of CAT, GPX, and Nrf2 expression and the addition of UCB further decreased GPX. The addition of UCB and HSA reverted the effects of OGD and UCB on gene expression. Conclusions: In an in vitro model of HIE in term infants, we did not observe neuroprotective changes of the expression of HO-1 and genes involved in antioxidant defenses. Conversely, in an in vitro model of HIE in preterm infants, we observed a harmful decrease of the expression of genes encoding for antioxidant enzymes.

Impact of sedative agents on cerebral blood flow and outcomes of hypoxic-ischemic encephalopathy in term infants

Мета роботи . Порівняти вплив морфіну та інших седативних засобів на стан мозкового кровотоку та результати лікування гіпоксично-ішемічної енцефалопатії у доношених новонароджених. Матеріали і методи . Досліджено 205 доношених новонароджених з гіпоксично-ішемічною енцефалопатією за Sarnat II-III ст. в терміні d”72 годин після пологів. Немовлята були стратифіковані за фармакологічним препаратом для медикаментозної седації під час проведення штучної вентиляції легень на групи із застосуванням морфіну (n=71) та групу порівняння (n=134), в яку увійшли оксибутират натрію, діазепам та дексмедетомідин в стандартних рекомендованих дозах. Проведений порівняльний аналіз впливу морфіну та інших лікарських засобів на стан церебральної перфузії та на результати лікування гіпоксично-ішемічної енцефалопатії. Результати і обговорення . Отримана достовірна відмінність поміж групами допплерівського індексу мозкового кровотоку RI у першу добу (0,64 [0,55-0,74] в групі морфіну та 0,68 [0,61-0,75] в групі контролю, р=0,037), і на третю добу лікування (відповідно 0,64 [0,55-0,70] проти 0,67 [0,61-0,75] при р=0,040), більш низькі показники САТ (51 [43-60] мм рт.ст. проти 56 [49-60] мм рт.ст. при р=0,017), більша у 2,2 рази частота судом (р=0,038) та вища майже у 2 рази концентрація протеїну S-100 на третю добу (р=0,029) у групі морфіну. Частота розвитку небажаного результату у вигляді церебральної лейкомаляції також була у 2 рази вище в групі морфіну (18,4%) ніж у контрольній групі (8,9%), хоча різниця виявилась недостовірною (р=0,051), але з очевидною тенденцією. Висновки . В гострому періоді гіпоксично-ішемічної енцефалопатії у доношених новонароджених застосування морфіну у якості препарату седативної дії у порівнянні з іншими фармакологічними препаратами призводить до низки негативних ефектів стосовно впливу на церебральну перфузію та на кінцеві результати лікування.

Impact of inotropes on cerebral blood flow in acute period of severe hypoxic-ischemic encephalopathy in term infants

OBJECTIVE. To determine impact of dopamine and dobutamine administration on cerebral blood flow in acute period of severe hypoxic-ischemic encephalopathy in neonates.MATERIALS AND METHODS. Data of 205 term infants with Apgar score at birth of 7 or less and Sarnat stage II-III collected during 72 hours of life. The relationships between mean blood pressure, RI and PI using dopamine and dobutamine during the first three days of the acute period of severe hypoxic-ischemic encephalopathy were analyzed.RESULTS AND DISCUSSION. During first three days of treatment no significant difference was found in mean blood pressure and cerebral blood flow administering dobutamine or combination of dobutamine and dopamine as inotropic support.In the acute period of HIE comparing to dobutamine if dopamine administered Resistant Index of cerebral arteries (RI) changed negatively, namely: dopamine administration on Day 1 of treatment led to decrease in RI during the first day of treatment (p = 0.021). The use of dopamine in 2nd day led to decrease in RI on 2nd day (p = 0.033) as well as on the 3rd day of the study (p = 0.016). The using of dopamine during the 3rd day was associated with decrease in the Pulsatile Index (PI) in the 3rd day of the study (p = 0.023).CONCLUSIONS. The administration of single dopamine or in combination with dobutamine leads to deterioration of cerebral perfusion, namely, a significant decrease in the resistance of the cerebral vessels, which is an unwanted prognostic sign for the short-term outcomes and complications of HIE.

Diagnostic and predictable values for doppler indices of cerebral blood flow in acute period of severe hypoxic-ischemic encephalopathy in term infants

OBJECTIVE. To determine diagnostic and predictable values for Doppler indices of cerebral blood flow in acute period of severe hypoxic-ischemic encephalopathy in neonates.MATERIALS AND METHODS. Data of 205 term infants with Apgar score at birth of 7 or less and Sarnat stage II-III was collected during d”72 hours of life. The correlation between RI and PI indices and Glasgow Coma Scale, serum protein S-100, seizures, confirmed by the aEEG, was analyzed, as well as prognostic model for unwanted development of neurological complications such as cerebral leukomalacia.RESULTS AND DISCUSSION. In the acute period of HIE Resistive Index (RI) and Pulsatile Index (RI), measured in the anterior cerebral artery on Day 3 after the end of the therapeutic hypothermia and brain reperfusion, reliably correlate with the serum concentration of brain damage marker protein S-100 (r=-0.2; p=0.037 and r=-0.2; p=0.039 respectively) as well as risk of cerebral leukomalacia (p=-0.13; p=0.016). The prognostic model based on the values of RI, PI, S-100 and GCS with sensitivity of 33% and 100% specificity predicts potential risk of leukomalacia after severe HIE in 32.7% – 42.1%.CONCLUSION. The evaluation of Doppler indices of cerebral blood flow RI and PI in the acute period of hypoxic ischemic encephalopathy in the term newborns has a significant diagnostic and predictable value and correlates with the severity and short-term clinical follow-up of HIE.

Prognostic values of serum neuronal biomarkers NSE and protein S-100 in acute period of severe hypoxic-ischemic encephalopathy in term infants

It remains unclear if the serum concentrations of neuron-specific enolase (NSE) and protein S-100 correlate with severity and possible complications of hypoxic ischemic encephalopathy (HIE) as well as monitoring parameters of cerebral perfusion and central hemodynamics in term newborns.The aim of research. To determine diagnostic and predictable values of NSE and protein S-100 in acute period of severe hypoxic-ischemic encephalopathy in neonates.Materials and methods. Data of 89 term infants with Apgar score at birth of seven or less and Sarnat stage II-III was collected during ≤72 hours of life. The correlation between NSE, S-100 and Glasgow Coma Scale, seizures, confirmed by the aEEG, the unwanted development of neurological complications such as cerebral leukomalacia, and the short-term clinical results were analyzed.Result. In acute period of HIE the concentration of serum neuronal biomarkers S-100 and NSE proteins substantially exceeds the reference values for the first hours after labor and exceeds the normal range until the 5th day of life. The dynamics of these data significantly changes during this period. Mostly diagnostically and prognostically significant the measurement of biomarkers was on the 3rd day of treatment, immediately after the end of the therapeutic hypothermia, at the beginning of rewarming and brain reperfusion, when both indicators were most closely correlated with the assessment of the GCS: NSE (r=-0.3; p=0.002 ) and S-100 (r=-0.3; p=0.003). The value of S-100 on day 1 correlating with the following unwanted development of leukomalacia is above 1.8 μg/L (p=0.002), which is more than 3 times higher from the reference level of 0.51 μg/L given by Simon-Pimmel J. (2017) for term newborns.Conclusion. The evaluation of the serum concentrations of protein S-100 and neuron-specific enolase in the acute period of hypoxic ischemic encephalopathy in the term newborns has a significant diagnostic and predictable value and correlates with the severity and short-term clinical results of HIE

Mild prenatal hypoxia-ischemia leads to social deficits and central and peripheral inflammation in exposed offspring

Hypoxic-ischemic encephalopathy (HIE) resulting from intrauterine or perinatal hypoxic-ischemia (HI) is a leading cause of long-term neonatal neurodisability. While most studies of long-term outcome have focused on moderate and severe HIE in term infants, recent work has shown that those with mild HIE may have subtle neurological impairments. However, the impact of mild HI on pre-term infants is much less clear given that pre-term birth is itself a risk factor for neurodisability. Here we show that mild HI insult alters behaviour, inflammation and the corticosterone stress response in a rat model of pre-term HIE. Mild HI exposure led to social deficits in exposed offspring at postnatal day 30, without impairments in the novel object recognition test nor in the open field test. This was also accompanied by elevations in circulating adrenocorticotropic hormone and corticosterone indicating an exaggerated stress response. There were also elevations in il-1β and il-6 but not tnf-α mRNA and protein in the brain and blood samples. In summary we find that a mild HI exposure leads to social deficits, central and peripheral inflammation, and an abnormal corticosterone response which are three core features of autism spectrum disorder. This shows that mild HI exposure may be a risk factor for an abnormal neurodevelopmental outcome in pre-term offspring.

Pharmacotherapy for Neonatal Seizures: Current Knowledge and Future Perspectives.

Seizures are the most common neurological emergencies in the neonatal period and are associated with poor neurodevelopmental outcomes. Seizures affect up to five per 1000 term births and population-based studies suggest that they occur even more frequently in premature infants. Seizures are a sign of an underlying cerebral pathology, the most common of which is hypoxic-ischaemic encephalopathy in term infants. Due to a growing body of evidence that seizures exacerbate cerebral injury, effective diagnosis and treatment of neonatal seizures is of paramount importance to reduce long-term adverse outcomes. Electroencephalography is essential for the diagnosis of seizures in neonates due to their subtle clinical expression, non-specific neurological presentation and a high frequency of electro-clinical uncoupling in the neonatal period. Hypoxic-ischaemic encephalopathy may require neuroprotective therapeutic hypothermia, accompanying sedation with opioids, anticonvulsant drugs or a combination of all of these. The efficacy, safety, tolerability and pharmacokinetics of seven anticonvulsant drugs (phenobarbital, phenytoin, levetiracetam, lidocaine, midazolam, topiramate and bumetanide) are reviewed. This review is focused only on studies reporting electrographically confirmed seizures and highlights the knowledge gaps that exist in optimal treatment regimens for neonatal seizures. Randomised controlled trials are needed to establish a safe and effective treatment protocol for neonatal seizures.

Changes in pulmonary arterial pressure in term‐infants with hypoxic–ischemic encephalopathy

Hypoxic-ischemic encephalopathy (HIE) is an important complication that results from birth asphyxia or some other adverse conditions and has a high risk of neonatal morbidity and mortality. It is unclear, however, whether the elevated pulmonary arterial pressure (PAP) can aggravate the condition and prognosis of HIE. The purpose of the present study was to investigate the relationship between the changes of PAP and HIE in term infants after birth asphyxia. The left/right ventricle pre-ejection phase (LPEP/RPEP), left/right ventricle ejection time (LVET/RVET) and the ratios of LPEP/LVET and RPET/RVET were evaluated in 40 term infants with HIE and 40 healthy controls on days 1, 3, 7, and 12-14 after birth using echocardiogram. PAP such as pulmonary arterial diastolic pressure (PADP, mmHg), pulmonary arterial resistance (PAR, mmHg), and pulmonary arterial resistance/systemic resistance ratio (PAR/RS) was calculated using these indexes. Patient mortality was also evaluated. PADP, PAR, and PAR/RS were significantly higher in HIE patients than in healthy controls during the first week after birth, particularly in severe-degree HIE patients. And until the end of the first week of life, these indexes may return to the levels of healthy controls. Persistent fetal circulation (PFC) was found in nine patients (7/16 severe, 2/12 moderate HIE patients), and non-PFC was found in mild HIE patients. Two patients with PFC died. No patients without PFC died. The course of HIE was longer in patients with pulmonary hypertension than in those without. Increased PAP is an important pathophysiological process that may influence the course and prognoses of HIE in infants after birth asphyxia, particular in severe HIE patients who often have PFC. Thus it is important to assess changes in PAP using echocardiography.

Symptomatic Parieto-Occipital Epilepsy as Sequela of Perinatal Asphyxia

Perinatal hypoxic-ischemic encephalopathy in term infants has been well-documented as a cause of selective brain damage over the parasagittal brain regions in cases of partial asphyxia. We describe 10 patients (7 boys, 3 girls) who developed normally after perinatal asphyxia, and who later experienced parieto-occipital epilepsy. We retrospectively reviewed medical records, electroencephalograms, and neuroimaging findings. All patients had a history of perinatal asphyxia requiring intensive care. Subsequent developmental milestones were apparently normal. Seizures started at ages ranging from 10 to 168 months (mean, 72 months). The seizures comprised complex partial seizures with visual symptomatology in 5 cases, complex partial seizures without visual symptomatology in 4 cases, and focal motor seizures with secondary generalization in the remaining case. Brain magnetic resonance imaging demonstrated localized parieto-occipital lesions in 9 cases, and normal findings in the remaining one. Electroencephalograms revealed predominantly occipital foci in 8. In all patients, the epileptogenic foci involved either unilateral or bilateral parieto-occipital regions. Intelligence quotients and visuospatial cognitive functions were impaired in 7 patients. Seizures were finally controlled in only 4 patients. Symptomatic parieto-occipital epilepsy caused by mild perinatal hypoxic-ischemic encephalopathy is sometimes pharmaco-resistant and accompanied by mild cognitive and visuospatial impairments.

Whole body hypothermia for the treatment of hypoxic-ischaemic encephalopathy in term infants – a safety study in Hungary

Hypoxic-ischaemic encephalopathy is a major cause of long-term morbidity and mortality in term infants. Prolonged systemic hypothermia is a promising new approach for reducing brain damage in neonates. The aim of the open cohort-series clinical study was to collect data about the safety and technical feasibility of the hypothermia treatment in Hungary before joining to a randomised efficacy trial. The authors treated 28 asphyxiated term neonates with hypothermia between 2003 and 2005. Hypothermia (rectal temperature 33-34 degrees C) was maintained for 72 hours during continuous morphine analgesia. For historical control group 23 asphyxiated neonates were selected treated with standard therapy between 1996 and 2002. Entry criteria were the following: a 5-minute Apgar score 5 or less, the evidence of serious metabolic acidosis in the first hour of life (a BE of 15 mmol/l) and clinical sign of encephalopathy at the same time. Routine laboratory measurements of liver enzymes, renal functions, blood cell count, head ultrasound were performed daily. The anthropometric and clinical parameters (Apgar, pH, BE, neurological signs of encephalopathy) of the hypothermia and control infants were similar. There were no significant differences between the mortality of the hypothermia (10/28 36%) and the control (10/21 48%) groups. The clinical parameters (laboratory values, abnormality on the head ultrasound, incidence of serious hypotension, hypoglycaemia, bleeding, need for cardiovascular support, oliguria) and the neurological outcome after 1.5-2 year follow-up were also similar. This study demonstrated that prolonged whole body hypothermia of the asphyxiated neonate is safe and not associated with increased mortality and morbidity up to 18 month of age.

The Continuing Fall in Incidence of Hypoxic-Ischaemic Encephalopathy in Term Infants

Objective To examine trends in incidence of hypoxic-ischaemic encephalopathy in term infants over a twenty-one year period. Design A retrospective analysis of medical records of all term infants admitted to a neonatal unit with hypoxic-ischaemic encephalopathy during the years 1992–1996 (period C) and a comparison with data from the years 1976–1980 (period A) and 1984–1988 (period B) from the same unit (previously published1). Setting A District Health Authority in Central England serving a population of about 450,000. Sample All term infants admitted with clinical features of hypoxic-ischaemic encephalopathy. Main outcome measures Incidence of three grades of hypoxic-ischaemic encephalopathy, disability and mortality. Results In each five year period there were similar numbers of births. Over the time-span of this study the stillbirth rate and neonatal mortality rate has consistently fallen. The overall incidence of hypoxicischaemic encephalopathy in term infants was significantly lower (P < 0.001; OR 0.42 CI 0.29–0.59) in the present study period (C) compared with the earlier study period B (1.9 vs 4.6 per 1000 total live births). The fall in moderately and severely affected infants between the present and the first study period was significant (1.2 vs 2.6 per 1000 total live births, P < 0.001: OR 0.46 CI 0.29–0.72). The number of deaths and the incidence of cerebral palsy in survivors fell progressively over the 21 years spanned by this study. Conclusion This study shows that the incidence of hypoxic-ischaemic encephalopathy and its sequelae in term infants has fallen significantly. The use of cardiotocography and caesarean section rates have risen but the relative contributions of changes in clinical practice are uncertain.

The continuing fall in incidence of hypoxic‐ischaemic encephalopathy in term infants

To examine trends in incidence of hypoxic-ischaemic encephalopathy in term infants over a twenty-one year period. A retrospective analysis of medical records of all term infants admitted to a neonatal unit with hypoxic-ischaemic encephalopathy during the years 1992-1996 (period C) and a comparison with data from the years 1976-1980 (period A) and 1984-1988 (period B) from the same unit (previously published). A District Health Authority in Central England serving a population of about 450,000. All term infants admitted with clinical features of hypoxic-ischaemic encephalopathy. Incidence of three grades of hypoxic-ischaemic encephalopathy, disability and mortality. In each five year period there were similar numbers of births. Over the time-span of this study the stillbirth rate and neonatal mortality rate has consistently fallen. The overall incidence of hypoxic-ischaemic encephalopathy in term infants was significantly lower (P < 0.001; OR 0.42 CI 0.29-0.59) in the present study period (C) compared with the earlier study period B (1.9 vs 4.6 per 1,000 total live births). The fall in moderately and severely affected infants between the present and the first study period was significant (1.2 vs 2.6 per 1,000 total live births, P < 0.001: OR 0.46 CI 0.29-0.72). The number of deaths and the incidence of cerebral palsy in survivors fell progressively over the 21 years spanned by this study. This study shows that the incidence of hypoxic-ischaemic encephalopathy and its sequelae in term infants has fallen significantly. The use of cardiotocography and caesarean section rates have risen but the relative contributions of changes in clinical practice are uncertain.

Hypoxic-ischemic encephalopathy in term infants: diagnosis and prognosis evaluated by ultrasound.

The results of cranial ultrasonography in 32 term infants who had hypoxic-ischemic encephalopathy (HIE) and in 26 control infants were reviewed. Small or nonvisualized ventricles were present in 94% of the patients with HIE and in 62% of the control subjects. In 20 of the 32 patients (63%) with HIE, ultrasound demonstrated parenchymal abnormalities; the most common finding was periventricular hyperechogenicity (12/32 patients). There was a single false positive result in the control group. Fifty per cent of patients with HIE who had abnormalities demonstrated on ultrasonograms died (within 15 days of birth), whereas none of the infants who had normal ultrasound findings died. Moreover, 80% of surviving patients who had abnormal ultrasound findings had residual neurological deficits versus only 11% of those with normal ultrasound findings. Our results indicate that ultrasound is effective in detecting parenchymal changes in patients with HIE, parenchymal echoes are a more reliable sign of HIE than ventricular size, and the finding of parenchymal lesions on ultrasound scans appears to be predictive of abnormal motor development.

Factors affecting outcome in hypoxic-ischemic encephalopathy in term infants.

Forty-nine term infants were prospectively shown to have hypoxic-ischemic encephalopathy (HIE). All infants survived the neonatal period, and all but two infants (seen at 12 months) were followed up to at least 27 months of age. Factors that significantly correlated with outcome included the Sarnat encephalopathy stage and the occurrence of intractable seizures not controlled by phenobarbital sodium alone. There was no association between the one- or five-minute Apgar score, the need for early ventilation, the EEG, the occurrence of seizures, and the subsequent outcome. There was no significant difference in outcome for those infants who received dexamethasone sodium phosphate (n = 29) v those who did not receive the drug (n = 20). A review of 97 term infants with HIE from a regional perinatal program during a one-year period (1979), including 35 of the 49 infants in the present study, did show a significant increase in morbidity and mortality for transported infants.