Should Australia Adopt a Groningen Like Protocol?

Objective: To compare the umbilical artery lactate level in different grades of Hypoxic Ischemic Encephalopathy in neonates with perinatal asphyxia. Study Design: Cross-sectional study. Place and Duration of Study: Pak Emirates Military Hospital, Rawalpindi Pakistan, from Dec 2021 to Feb 2022. Methodology: A group of 70 neonates with gestational age of 36 weeks (252 days) and above, who were reported to have any late deceleration, meconium staining of liquor, low 5 minute APGAR score and need for neonatal resuscitation for more than 1 minute, were selected and their umbilical artery lactate levels were measured. Neonates were classified into two groups by using Sarnet and Sarnet classification with Group-A having neonates with No or Mild Hypoxic Ischemic Encephalopathy and Group-B with Moderate to Severe Hypoxic Ischemic Encephalopathy. Results: A total of 70 patients were enrolled in the study with median gestational age of 267 days and mean weight of 2.70±0.60 kg. A total of 45 neonates were found to have No or mild Hypoxic Ischemic Encephalopathy (Group-A) with mean lactate level of 3.64±1.49 mmol/L and 25 diagnosed with moderate to severe Hypoxic Ischemic Encephalopathy (Group-B) had mean lactate level of 9.40±2.26 mmol/L. Mean lactate levels were significantly raised for Moderate to Severe Hypoxic Ischemic Encephalopathy (p≤0.005). Conclusions: The umbilical artery lactate level can be used as a predictor of moderate-to-severe Hypoxic Ischemic Encephalopathy in neonates suffering from perinatal asphyxia.

In The Netherlands, neonatal euthanasia has become a legal option and the Groningen Protocol contains an approach to identify situations in which neonatal euthanasia might be appropriate. In the 5...

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).

Objective To explore the clinical value of 3.0T nuclear magnetic resonance susceptibility weighted imaging in diagnosis of neonatal hypoxic ischemic encephalopathy, thus to provide guidance for the clinical. Methods From December 10, 2015 to December 10, 2017, 100 cases of neonatal hypoxic ischemic encephalopathy(observation group) and 100 cases of normal newborns in Lishui People's Hospital during the same period accepted health examination(control group) were selected in the research.All the cases received 3.0T magnetic resonance susceptibility weighted imaging, the diagnostic value of 3.0T MR susceptibility weighted imaging was observed. Results The ADC value of the observation group[(0.00 1 13±0.000 01)mm2/s]was significantly lower than that in the control group[(0.001 98±0.000 02)mm2/s](P<0.05). The neonatal ADC value of the mild group[(0.001 21±0.000 01)mm2/s]was significantly higher than that in the moderate group[(0.001 12±0.000 02)mm2/s]and the severe group[(0.001 02±0.000 03)mm2/s](P<0.05). ADC value was positively correlated with neonatal hypoxic ischemic encephalopathy, namely, the lower the ADC value, the more serious the neonatal hypoxic ischemic encephalopathy.The fractional anisotropy value and relative anisotropy value of newborn babies in the observation group were significantly higher than those in the control group(all P<0.05). Conclusion For neonatal hypoxic ischemic encephalopathy patients, 3.0T nuclear magnetic resonance susceptibility weighted imaging in the diagnosis is feasible, it can help the clinician to analyze the disease, and has positive significance to carry out the treatment. Key words: 3.0T MRI; Magnetic sensitive weighted imaging; Hypoxic ischemic encephalopathy; Newborn; Diagnosis

Therapeutic hypothermia for birth asphyxia in low-resource settings: a pilot randomised controlled trial

Optimal obstetric care reduces neonatal healthcare costs compared with substandard care in hypoxic-ischemic encephalopathy.

We aimed to correlate amplitude-integrated EEG (aEEG) in neonatal hypoxic ischemic encephalopathy (HIE) with early magnetic resonance imaging (MRI). In this retrospective study, 32 neonates over 35weeks' gestation with moderate/severe HIE who were treated with hypothermia were included. Early MRI scans and daily aEEG background were categorized to mild/normal, moderate, and severely abnormal. Time to sleep cycling was noted on aEEG. Mantel-Haenszel test for trends was used to explore associations between aEEG and MRI and outcome. LOESS regression was used for exploring the association of cycling with MRI scores. MRI was normal/mildly abnormal in 20 (63%) infants; in 9 (28%), moderately abnormal; and in 3 (9%), severely abnormal. Twenty-seven (84%) infants s urvived. MRI severity score was significantly associated with aEEG background score on the third and fourth days of life (p < 0.01). An increase in the MRI severity score was noted if sleep cycling appeared after the fifth day of life.Conclusions: Depressed aEEG at the third and fourth days of life and appearance of cycling beyond the fifth day of life are associated with cerebral MRI abnormalities and may be associated with increased risk of abnormal outcome. What is known: • Since therapeutic hypothermia has been shown to change long-term outcome, amplitude-integrated EEG in infants with hypoxic ischemic neonatal encephalopathy soon after birth have a limited predictive power for long-term outcome in treated infants. • Brain MRI after therapeutic hypothermia in the above infants has a significant predictive value for long-term outcome What is new: • Background amplitude-integrated EEG activity depression at the age of 3 and 4days and delay of appearance of cycling activity are associated with worse MRI scores and may be predictive of worse long-term outcome.

BackgroundNeonatal encephalopathy (NE) affects 2–4/1000 live births with outcomes ranging from negligible neurological deficits to severe neuromuscular dysfunction, cerebral palsy and death. Hypoxic ischemic encephalopathy (HIE) is the sub cohort of NE that appears to be driven by intrapartum events. Our objective was to identify antepartum and intrapartum factors associated with the development of neonatal HIE.MethodsHospital databases were searched using relevant diagnosis codes to identify infants with neonatal encephalopathy. Cases were infants with encephalopathy and evidence of intrapartum hypoxia. For each hypoxic ischemic encephalopathy case, four controls were randomly selected from all deliveries that occurred within 6 months of the case.ResultsTwenty-six cases met criteria for hypoxic ischemic encephalopathy between 2002 and 2014. In multivariate analysis, meconium-stained amniotic fluid (aOR 12.4, 95% CI 2.1–144.8, p = 0.002), prolonged second stage of labor (aOR 9.5, 95% CI 1.0–135.3, p = 0.042), and the occurrence of a sentinel or acute event (aOR 74.9, 95% CI 11.9-infinity, p < 0.001) were significantly associated with hypoxic ischemic encephalopathy. The presence of a category 3 fetal heart rate tracing in any of the four 15-min segments during the hour prior to delivery (28.0% versus 4.0%, p = 0.002) was more common among hypoxic ischemic encephalopathy cases.ConclusionProlonged second stage of labor and the presence of meconium-stained amniotic fluid are risk factors for the development of HIE. Close scrutiny should be paid to labors that develop these features especially in the presence of an abnormal fetal heart tracing. Acute events also account for a substantial number of HIE cases and health systems should develop programs that can optimize the response to these emergencies.

Neonatal encephalopathy (NE) is a pathological condition affecting long‐term neurodevelopmental outcomes. Hypothermia is the only therapeutic option, but does not always improve outcomes; hence, researchers continue to hunt for pharmaceutical compounds. Melatonin treatment has benefitted neonates with hypoxic–ischemic (HI) brain injury. However, unlike animal models that enable the study of the brain and the pathophysiologic cascade, only blood is available from human subjects. Therefore, due to the unavailability of neonatal brain tissue, assumptions about the pathophysiology in pathways and cascades are made in human subjects with NE. We analyzed animal and human specimens to improve our understanding of the pathophysiology in human neonates. A neonate with NE who underwent hypothermia and enrolled in a melatonin pharmacokinetic study was compared to HI rats treated/untreated with melatonin. MicroRNA (miRNA) analyses provided profiles of the neonate's plasma, rat plasma, and rat brain cortexes. We compared these profiles through a bioinformatics tool, identifying Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways common to HI brain injury and melatonin treatment. After evaluating the resulting pathways and the literature, to validate the method, the key proteins expressed in HI brain injury were investigated using cerebral cortexes. The upregulated miRNAs in human neonate and rat plasma helped identify two KEGG pathways, glioma and long‐term potentiation, common to HI injury and melatonin treatment. A unified neonatal cerebral melatonin‐sensitive HI pathway was designed and validated by assessing the expression of protein kinase Cα (PKCα), phospho (p)‐Akt, and p‐ERK proteins in rat brain cortexes. PKCα increased in HI‐injured rats and further increased with melatonin. p‐Akt and p‐ERK returned phosphorylated to their basal level with melatonin treatment after HI injury. The bioinformatics analyses validated by key protein expression identified pathways common to HI brain injury and melatonin treatment. This approach helped complete pathways in neonates with NE by integrating information from animal models of HI brain injury.

(Obstet Gynecol. 2024;143(1):67–81. doi: 10.1097/AOG.0000000000005392) Neonatal hypoxic-ischemic encephalopathy (HIE) is a significant condition linked to mortality and long-term disabilities such as cognitive impairment, cerebral palsy, seizures, and sensory deficits. It falls under neonatal encephalopathy, a broader syndrome characterized by various neurologic dysfunctions, including altered consciousness, respiratory difficulties, and impaired reflexes. This syndrome can arise from multiple causes, including HIE, brain malformations, strokes, genetic disorders, and infections. HIE alone accounts for approximately half of neonatal encephalopathy cases, highlighting its clinical importance due to its association with serious outcomes. HIE can occur suddenly, without warning, and its treatment historically relied on supportive care alone. However, recent research highlights a critical time window in the first hours to days posthypoxia-ischemia, during which hypothermia therapy can mitigate brain injury. This article aims to inform obstetricians about neonatal encephalopathy, particularly HIE, and the role of hypothermia treatment.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a brain injury caused by perinatal asphyxia and is the main cause of neonatal death and chronic neurological diseases. Protection of neuron after hypoxic-ischemic (HI) brain injury is considered as a potential therapeutic target of HI brain injury. To date, there are no effective medicines for neonatal HI brain injury. Lycopene (Lyc), a member of the carotenoids family, has been reported to have anti-oxidative and anti-inflammatory effects. However, its effects and potential mechanisms in HI brain injury have not yet to be systematically evaluated. In this study, we investigated whether Lyc could ameliorate HI brain injury and explored the associated mechanism both in vivo and in vitro experiments. In vivo study, Lyc significantly reduced infarct volume and ameliorated cerebral edema, decreased inflammatory response, promoted the recovery of tissue structure, and improved prognosis following HI brain injury. In vitro study, results showed that Lyc reduced expression of apoptosis mediators in oxygen-glucose deprivation (OGD)-induced primary cortical neurons. Mechanistically, we found that Lyc-induced Nrf2/NF-κB pathway could partially reversed by Brusatol (an Nrf2 inhibitor), indicated that the Nrf2/NF-κB pathway was involved in the therapy of Lyc. In summary, our findings indicate that Lyc can attenuated HI brain injury in vivo and OGD-induced apoptosis of primary cortical neurons in vitro through the Nrf2/NF-κB signaling pathway.

Neonatal hypoxic-ischemic encephalopathy (HIE), the leading cause of neonatal encephalopathy (NE), primarily affects the central nervous system and is associated with multi-organ dysfunction (MOD) and long-term complications. Research often focuses on moderate to severe NE, with limited data on mild cases. To investigate the incidence and severity of MOD in neonates with mild NE and explore its association with HIE severity. Term neonates with NE related to HIE diagnosis between 2009 and 2023 were included. Sarnat staging was used to classify cases into mild and moderate/severe. MOD was assessed on days 1 and 3 post-birth through echocardiography, troponin levels, creatinine levels, urine output, and liver function tests. Among 452 neonates with HIE (185 mild, 267 moderate/severe), 57% had liver injury, 55% cardiac injury, and 44% kidney injury in the first day of life. Neonates with mild NE had a MOD rate of 23%, lower than the 37% observed in moderate/severe (p = 0.002). When compared to mild, infants with moderate/severe NE had significantly higher incidences of cardiac (69% vs. 31%; p < 0.001), renal (49% vs. 38%; p = 0.067), and hepatic abnormalities (65% vs. 45%; p = 0.005). This study highlights the risk of extra-cranial organ injury even in infants with mild NE, stressing the importance of monitoring all regardless of severity. Comprehensive study prospectivelyevaluating end-organ dysfunction in a cohort of neonates diagnosed with mild, moderate, and severe NE.

Background Hypoxic-ischemic encephalopathy (HIE) in neonates results from oxygen deprivation at birth, often leading to long-term neurological issues like cerebral palsy. Early detection is key to improving outcomes, but HIE remains a significant cause of neonatal complications. Here we aimto study the risk factors and predictors of outcome in moderate to severe HIE in inborn Term babies in the neonatal intensive care unit (NICU) Methods This prospective observational study was conducted in the NICUat a tertiary care center between August 2022 and July 2024. Forty term neonates diagnosed with moderate to severe HIE based on clinical and MRI findings were included. The study recorded antepartum, intrapartum, and postnatal risk factors, and neonatal outcomes were followed up. Results In this study of 40 term neonates with HIE, 27 (67.5%) were male, 30 (75%) had a birth weight <2.5 kg, and 27 (67.5%) were delivered by cesarean section. Socioeconomic analysis revealed that 17 (42.5%) were from poor backgrounds. Of the mothers, 12 (30%) were over 30 years oldand 19 (47.5%) used medications. Intrapartum factors included oligohydramnios in 13 (32.5%) and pregnancy-induced hypertension in 10 (25%). Postnatally, 28 (70%) required resuscitation, and 32 (80%) had a cord blood pH ≤7.0. MRI patterns showed 18 (45%) with basal ganglia/thalamus involvement and 22 (55%) with watershed lesions. At discharge, 39 (97.5%) were sent home, with 5 (12.5%) needing anti-seizure medications. No significant associations were found between MRI patterns and muscle tone or seizure activity. Conclusion This study highlights the complex interplay of maternal, intrapartum, and neonatal factors in the development of HIE.Identifying early risk factors is crucial for developing preventive and therapeutic strategies to reduce the burden of HIE-associated disabilities.

Introduction: Neonatal hypoxic-ischemic encephalopathy (HIE) is a very catastrophic condition that may result in severe neurologic deficits or even death. Neuroimaging with transcranial ultrasound (US) is a valuable tool in the workup of patients with HIE. The pattern of brain injury depends on the severity and duration of hypoxia and degree of brain maturation.1&#x0D; Aim: To study imaging spectrum of various stages of HIE&#x0D; Objective: To determine severity of HIE on basis of Neuro-sonography.&#x0D; Settings and Design: The study was conducted at J K Lone Paediatric hospital attached to SMS hospital. It is a Prospective study.&#x0D; Materials and Method: Pre term neonates having some history of hypoxia antenatally or perinatally like placental abruption, low Apgar at delivery, seizures coming to JK lone Paediatric Hospital attached to SMS hospital referred to Dept of Radiodiagnosis for evaluation of HIE were scanned using Transcranial ultrasound it included grayscale on Hitachi machine.&#x0D; Results- Different grades of HIE changes were witnessed. Out of 33 cases:&#x0D; 5 neonates were sonographically normal, 3 showed grade 1 GMH, 3 showed grade 2 GMH, 4 showed grade 3 GMH and 4 showed grade 4 . 3 neonates showed grade 1 PVL, 2 grade 2 PVL, 4 showed grade 3 PVL, 5 showed grade 4 PVL. In doppler findings of ACA, it was noted the RI (resistive index) was on the higher side.&#x0D; Conclusion: Neurosonography and doppler is very helpful non-invasive tool to detect early changes of HIE and assess severity and progression of hypoxic brain injury. &#x0D; Keywords: HIE, hypoxic brain injury, germinal matrix haemorrhage and periventricular leucomalacia

Therapeutic hypothermia remains the only proven treatment to improve mortality and morbidity in neonates with hypoxic–ischaemic encephalopathy (HIE).1 Preclinical models have demonstrated erythropoietin as a potential adjuvant therapy in neonatal HIE due to its neuroprotective and neuro-regenerative effects.1 The anti-inflammatory and anti-oxidant effects of erythropoietin promotes neurogenesis through remodelling of brain tissue after HIE.2 The neuroprotective effects of erythropoietin result from its binding to erythropoietin receptors on mature neurons and neuronal progenitors causing induction of antiapoptotic genes.2 The data from small clinical trials suggest that erythropoietin monotherapy for neonates with moderate-to-severe HIE reduces the risk of cerebral palsy and moderate-to-severe cognitive impairment.2, 3 Furthermore, erythropoietin with or without hypothermia demonstrated reduced risk of brain injury on MRI in two randomised control trials.2 Previous randomised control trials investigating erythropoietin in combination with therapeutic hypothermia have shown promising results of neuroprotective benefit although were limited by small sample size.2 A small randomised controlled trial by Saad et al.,4 which included 33 neonates with HIE demonstrated lower occurrence of clinically detectable seizures in the first week of life. Conversely, preclinical data in studies by Fan et al. and Fang et al. did not demonstrate positive effects of erythropoietin in HIE.1 Furthermore, the study conducted by Wassink et al.5 in near-term fetal sheep concluded that high-dose erythropoietin may not be an effective adjuvant therapy in HIE.5 This phase III study by Wu et al. concluded no improvement in neurodevelopmental outcome in neonates with HIE following combined erythropoietin intervention and therapeutic hypothermia compared with placebo. Behavioural abnormalities were found to be four times greater in the erythropoietin group compared with placebo; however, this will need further investigation by a follow-up study beyond 36 months of age. The study concluded a higher risk of serious adverse events in the erythropoietin group compared to the placebo group. The conclusions regarding adverse effects from the study by Wu et al. are in contrast with prior systematic reviews conducted by Razak and Hussain2 and Ivain et al.6 which demonstrated erythropoietin monotherapy not to be associated with significant adverse outcomes or complications. Furthermore, Oorschot et al.1 and Garg et al.7 showed no adverse effects in studies of combined erythropoietin and therapeutic hypothermia in the treatment of babies with HIE. A wide range of adverse effects were monitored during different clinical trials.1, 2, 6, 7 Wu et al. combined various adverse events which included 'death, systemic hypertension, polycythaemia, disseminated intravascular coagulation, major venous or arterial thrombosis, pulmonary hypertension, intracranial haemorrhage, cardiopulmonary arrest or other unexpected life-threatening event' into the composite outcome of 'serious adverse events'. The results of this single randomised control trial showing contrasting results compared with prior meta-analysis studies in terms of adverse events could be due to variation in parameters and classifications used in different trials. The results of the ongoing trial 'Erythropoietin for Hypoxic Ischaemic Encephalopathy in Newborns' (PAEAN) is likely to provide more information on erythropoietin's adverse effects and neuroprotective effects.8 Further larger-scale studies on the use of erythropoietin without hypothermia would be important, particularly in resource-limited countries where the option of therapeutic hypothermia is limited and most injury related to HIE is sub-acute.9 URL LINK: https://ebneo.org/ebneo-commentary-epo-for-hie None.