Evoked potentials predict psychomotor development in neonates with normal MRI after hypothermia for hypoxic-ischemic encephalopathy

Hypothermia for Hypoxic-ischemic Encephalopathy: Second-generation Trials to Address Gaps in Knowledge

Selective Head Cooling with Mild Systemic Hypothermia after Neonatal Hypoxic-Ischemic Encephalopathy: A Multicenter Randomized Controlled Trial in China

Describe the association between cardiac dysfunction and death or moderate-to-severe abnormalities on brain magnetic resonance imaging (MRI) in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE). Retrospective study in neonates with moderate or severe HIE undergoing therapeutic hypothermia between 2008 and 2017. Primary outcome was death or moderate-to-severe brain injury using the Barkovich score. Conventional and speckle-tracking echocardiography measures were extracted from available echocardiograms to quantify right (RV) and left (LV) ventricular functions. A total of 166 newborns underwent therapeutic hypothermia of which 53 (36.5%) had echocardiography performed. Ten (19%) died prior to hospital discharge, and 11 (26%) had moderate-to-severe brain injury. There was no difference in chronologic age at echocardiography between the normal and adverse outcome groups (22 [±19] vs. 28 [±21] hours, p = 0.35). Cardiac findings in newborns with abnormal outcome included lower systolic and diastolic blood pressure (BP) at echocardiography (p = 0.004) and decreased tricuspid annular plane systolic excursion (a marker of RV systolic function; p = 0.01), while the ratio of systolic pulmonary artery (PA) pressure to systolic BP indicated isosystemic pressures (>2/3 systemic) in both groups. A multilogistic regression analysis, adjusting for weight and seizure status, indicated an association between abnormal outcome and LV function by longitudinal strain, as well as by ejection fraction. Newborns who died or had moderate-to-severe brain injury had a higher incidence of cardiac dysfunction but similar PA pressures when compared with those who survived with mild or no MRI abnormalities. · Newborns with HIE with functional LV/RV dysfunction are at risk for death or brain injury.. · All neonates with HIE had elevated pulmonary pressure, but neonates with poor outcome had RV dysfunction.. · When evaluating newborns with HIE by echocardiography, beyond estimation of pulmonary pressure, it is important to assess biventricular function..

Renal Saturation and Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia

Neonatal encephalopathy affects 2–5/1000 live births and hypoxic ischaemic encephalopathy (HIE) is the major cause1. Therapeutic hypothermia reduces brain injury and improves the neurodevelopmental outcome. We are sharing our local experience in therapeutic hypothermia in the form of a case series of two patients. Our incidence of moderate to severe HIE is 0.6/1000 live births. Both patients were cooled for 72 hours. The challenges faced were mainly in the time taken for achieving the target temperature and the time needed for re-warming, which varied from one to six hours and 4–24 hours, respectively. Complications like hyponatremia, hypokalemia, sinus bradycardia and thrombocytopenia were noted. Amplitude integrated electroencephalogram (aEEG) remained abnormal post cooling for both babies. Clinical markers, aEEG and MRI head findings combine to prognosticate well for the neurodevelopmental outcomes. We need to be familiar with the protocol for timely implementation of cooling, whichever the cooling method. Concentrating these high-risk cases in selected tertiary centres capable of instituting cooling as well as long-term follow-up will ensure better outcomes.

Data for 205 neonates from the multicenter National Institute of Child Health trial of hypothermia in hypoxic-ischemic encephalopathy (HIE) were analyzed by using clinical and laboratory variables obtained in the NICUs within 6 hours of birth, with death or moderate/severe disability at 18-22 months or death as the outcomes.

Background:Neonatal seizures represent a significant clinical challenge with marked socioeconomic disparities in prevalence, ranging from 1-3 per 1,000 live births in high-income nations to 36-90 per 1,000 in low- and middle-income countries. Neonates present unique pharmacological challenges due to their rapidly changing physiology, requiring careful consideration in antiepileptic drug administration. Purpose:This review analyzes the pharmacokinetic variability of antiepileptic drugs in neonates and infants, understanding the factors that contribute to dose-dependent adverse reactions and the importance of individualized dosing approaches. Methods:A comprehensive review of current literature was conducted across multiple electronic databases including PubMed, Embase, Cochrane Library and Medscape examining the pharmacokinetic properties of antiepileptic medications in neonates, impact of physiological factors, therapeutic interventions, and long-term neurological consequences. Special attention was given to the effects of therapeutic hypothermia and other intensive care interventions on drug disposition. Results:Neonatal physiology significantly impacts antiepileptic drug disposition through multiple mechanisms, including variations in distribution, clearance, protein binding, and enzyme activity. Therapeutic interventions, particularly hypothermia in hypoxic-ischemic encephalopathy, can substantially alter pharmacokinetic parameters and drug clearance. Animal studies suggest potential neurodevelopmental impacts of early antiepileptic drug exposure, though establishing direct causality remains challenging due to the concurrent effects of seizures on brain development.Conclusion: The unique physiological characteristics of neonates necessitate an individualized approach to antiepileptic drug dosing. The complex interplay between developmental factors, therapeutic interventions, and drug disposition highlights the importance of careful monitoring and dose adjustment based on patient-specific factors. Further research is needed to better understand the long-term neurodevelopmental implications of early antiepileptic drug exposure.

A major challenge in modern neonatal care is to further improve outcomes after therapeutic hypothermia for hypoxic ischemic encephalopathy. In this study we tested whether extending the duration of cooling might reduce white matter damage. Term-equivalent fetal sheep (0.85 gestation) received either sham ischemia followed by normothermia (n = 8) or 30 minutes of bilateral carotid artery occlusion followed by three days of normothermia (n = 8), three days of hypothermia (n = 8) or five days of hypothermia (n = 8) started three hours after ischemia. Histology was assessed 7 days after ischemia. Ischemia was associated with loss of myelin basic protein (MBP) and Olig-2 positive oligodendrocytes and increased Iba-1-positive microglia compared to sham controls (p < 0.05). Three days and five days of hypothermia were associated with a similar, partial improvement in MBP and numbers of oligodendrocytes compared to ischemia-normothermia (p < 0.05). Both hypothermia groups had reduced microglial activation compared to ischemia-normothermia (p < 0.05). In the ischemia-five-day hypothermia group, but not ischemia-three-day, numbers of microglia remained higher than in sham controls (p < 0.05). In conclusion, delayed cerebral hypothermia partially protected white matter after global cerebral ischemia in fetal sheep. Extending cooling from 3 to 5 days did not further improve outcomes, and may be associated with greater numbers of residual microglia.

Infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy are at risk for rebound seizures during and after the rewarming phase. We report a term male infant who was cooled for hypoxic ischemic encephalopathy. He developed electrographic seizures for the first time during the warming phase, which continued in the hours after rewarming. The seizures stopped within 30 minutes of recooling to 33.5°C without anticonvulsant medication. He was uneventfully cooled for an additional 24 hours and then rewarmed with no recurrence of seizures. Hypothermia appeared to have an antiepileptic effect in this case and may be worthy of additional investigation as an adjunct to antiepileptic drug therapy in newborns.

Diffusion-weighted imaging performed shortly after brain injury has been shown to facilitate visualization of acute corticospinal tract injury known as "pre-Wallerian degeneration." The aim of this study was to determine whether diffusion restriction in the corticospinal tract and corpus callosum occurs within the first 2weeks after birth in neonates with neonatal hypoxic-ischemic encephalopathy. We enrolled a consecutive series of 66 infants diagnosed with hypoxic-ischemic encephalopathy who underwent MRI. We evaluated diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) values to assess the presence of restricted diffusion in the corticospinal tract and corpus callosum. Next, we compared ADC values in the corticospinal tract and in the splenium and genu of the corpus callosum of infants with abnormal pattern on MRI with those of control infants, who showed a normal pattern on MRI. We attempted to follow all infants with hypoxic-ischemic encephalopathy until 18months of age and assess them using a standardized neurologic examination. After exclusions, we recruited 25 infants with abnormal MRI and 20 with normal MRI (controls). Among these 45 neonates, pre-Wallerian degeneration was visualized in the corticospinal tract in 10 neonates and in the corpus callosum in 12. The ADC values in the corticospinal tract in the first week were significantly lower than they were in the second week. Infants with pre-Wallerian degeneration in the corticospinal tract showed an unfavorable outcome. Pre-Wallerian degeneration was visualized in the corticospinal tract and corpus callosum and was associated with extensive brain injury caused by hypoxic-ischemic encephalopathy. The changes in signal were observed to evolve over time within the first 2weeks. The clinical outcome of infants having pre-Wallerian degeneration in the corticospinal tract was unfavorable.

The biochemical composition and structure of the brain are in a rapid change during the exuberant stage of fetal and neonatal development. 1H‐MRS is a noninvasive tool that can evaluate brain metabolites in healthy fetuses and infants as well as those with neurological diseases. This review aims to provide readers with an understanding of 1) the basic principles and technical considerations relevant to 1H‐MRS in the fetal‐neonatal brain and 2) the role of 1H‐MRS in early fetal‐neonatal development brain research. We performed a PubMed search to identify original studies using 1H‐MRS in neonates and fetuses to establish the clinical applications of 1H‐MRS. The eligible studies for this review included original research with 1H‐MRS applications to the fetal‐neonatal brain in healthy and high‐risk conditions. We ran our search between 2000 and 2023, then added in several high‐impact landmark publications from the 1990s. A total of 366 results appeared. After, we excluded original studies that did not include fetuses or neonates, non‐proton MRS and non‐neurological studies. Eventually, 110 studies were included in this literature review. Overall, the function of 1H‐MRS in healthy fetal‐neonatal brain studies focuses on measuring the change of metabolite concentrations during neurodevelopment and the physical properties of the metabolites such as T1/T2 relaxation times. For high‐risk neonates, studies in very low birth weight preterm infants and full‐term neonates with hypoxic–ischemic encephalopathy, along with examining the associations between brain biochemistry and cognitive neurodevelopment are most common. Additional high‐risk conditions included infants with congenital heart disease or metabolic diseases, as well as fetuses of pregnant women with hypertensive disorders were of specific interest to researchers using 1H‐MRS.Evidence Level1Technical EfficacyStage 2

Bilateral loss of cortical SEPs predict severe MRI lesions in neonatal hypoxic ischemic encephalopathy treated with hypothermia

The obstetric and neonatal technological advances have changed the frequency and syndromic classification of perinatal brain lesions. To study all prevalent patients during 1996, with perinatal or late intrauterine brain lesions, in the outpatient neuropediatric clinic at our hospital. Selection of patients according to neuroimaging findings, and/or neurological sequela with documented perinatal antecedent. a normal MRI, brain lesions of doubtful origin, or uncertain sequela with normal CT or echography studies. Descriptive study, and also analytical, using logistic regression to study the relationship between antecedents and sequela. A total of 111 patients with: brain lesions due to hypoxic-ischemic encephalopathy (22 cases), lesions due to prematurity (29), late intrauterine infection or neonatal meningitis as the only cause of fixed neurological impairment (12), unexpected vascular brain lesions during the neonatal period (11), late intrauterine brain lesions (37). The neurological sequela observed were: cerebral palsy (68%), epilepsy (47%), mental retardation (45%), learning disorders in (34%) of those of school age and free from mental retardation, strabism (26%), microcephaly (19%), visual impairment (14%), hyperkinesis (10%). The neuroimaging findings were: focal lesions (45%), hydrocephaly (28%), intraventricular haemorrhage (22%), white matter lesions (24%), venous thrombosis (2%). The multivariable analysis showed, as the most noticeable finding, the relationship between the antecedent of mechanical ventilation and late development of hyperkinesis (OR: 10), in this sample of patients with severe sequela. Three patients should be noted: a case of late-onset dystonia secondary to a late intrauterine brain lesion, a child with exclusively cerebellar symptoms due to a destructive cerebellar lesion of prenatal onset, and a patient with an acquired perinatal biopercular lesion and pseudobulbar palsy as the only long-term sequelae.

Seizures in the neonatal period are associated with increased mortality and morbidity. Bedside amplitude-integrated electroencephalography (aEEG) has facilitated the detection of electrographic seizures; however, whether these seizures should be treated remains uncertain. To determine if the active management of electrographic and clinical seizures in encephalopathic term or near-term neonates improves survival free of severe disability at 2 years of age compared with only treating clinically detected seizures. This randomized clinical trial was conducted in tertiary newborn intensive care units recruited from 2012 to 2016 and followed up until 2 years of age. Participants included neonates with encephalopathy at 35 weeks' gestation or more and younger than 48 hours old. Data analysis was completed in April 2021. Randomization was to an electrographic seizure group (ESG) in which seizures detected on aEEG were treated in addition to clinical seizures or a clinical seizure group (CSG) in which only seizures detected clinically were treated. Primary outcome was death or severe disability at 2 years, defined as scores in any developmental domain more than 2 SD below the Australian mean assessed with Bayley Scales of Neonate and Toddler Development, 3rd ed (BSID-III), or the presence of cerebral palsy, blindness, or deafness. Secondary outcomes included magnetic resonance imaging brain injury score at 5 to 14 days, time to full suck feeds, and individual domain scores on BSID-III at 2 years. Of 212 randomized neonates, the mean (SD) gestational age was 39.2 (1.7) weeks and 122 (58%) were male; 152 (72%) had moderate to severe hypoxic-ischemic encephalopathy (HIE) and 147 (84%) had electrographic seizures. A total of 86 neonates were included in the ESG group and 86 were included in the CSG group. Ten of 86 (9%) neonates in the ESG and 4 of 86 (4%) in the CSG died before the 2-year assessment. The odds of the primary outcome were not significantly different in the ESG group compared with the CSG group (ESG, 38 of 86 [44%] vs CSG, 27 of 86 [31%]; odds ratio [OR], 1.83; 95% CI, 0.96 to 3.49; P = .14). There was also no significant difference in those with HIE (OR, 1.77; 95% CI, 0.84 to 3.73; P = .26). There was evidence that cognitive outcomes were worse in the ESG (mean [SD] scores, ESG: 97.4 [17.7] vs CSG: 103.8 [17.3]; mean difference, -6.5 [95% CI, -1.2 to -11.8]; P = .01). There was little evidence of a difference in secondary outcomes, including time to suck feeds, seizure burden, or brain injury score. Treating electrographic and clinical seizures with currently used anticonvulsants did not significantly reduce the rate of death or disability at 2 years in a heterogeneous group of neonates with seizures. http://anzctr.org.au Identifier: ACTRN12611000327987.

Maternal alcoholism and neonatal hypoxia-ischemia: Neuroprotection by stilbenoid polyphenols