Therapeutic Hypothermia in Neonatal Hypoxic Ischemic Encephalopathy: Electrographic Seizures and Magnetic Resonance Imaging Evidence of Injury

Therapeutic hypothermia is the standard-of-care treatment for infants diagnosed with moderate-to-severe hypoxic-ischemic encephalopathy (HIE). MRI for assessing brain injury is usually performed after hypothermia because of logistical challenges in bringing acutely sick infants receiving hypothermia from the neonatal intensive care unit (NICU) to the MRI suite. Perhaps examining and comparing early cerebral oxygen metabolism disturbances to those after rewarming will lead to a better understanding of the mechanisms of brain injury in HIE and the effects of therapeutic hypothermia. The objectives were to assess the feasibility of performing a novel T2-relaxation under spin tagging (TRUST) MRI technique to measure venous oxygen saturation very early in the time course of treatment, 18-24h after the initiation of therapeutic hypothermia, to provide a framework to measure neonatal cerebral oxygen metabolism noninvasively, and to compare parameters between early and post-hypothermia MRIs. Early (18-24h after initiating hypothermia) MRIs were performed during hypothermia treatment in nine infants with HIE (six with moderate and three with severe HIE). Six infants subsequently had an MRI after hypothermia. Mean values of cerebral blood flow, oxygen extraction fraction, and cerebral metabolic rate of oxygen from MRIs during hypothermia were compared between infants with moderate and severe HIE; and in those with moderate HIE, we compared cerebral oxygen metabolism parameters between MRIs performed during and after hypothermia. During the initial hypothermia MRI at 23.5±5.2h after birth, infants with severe HIE had lower oxygen extraction fraction (P=0.04) and cerebral metabolic rate of oxygen (P=0.03) and a trend toward lower cerebral blood flow (P=0.33) compared to infants with moderate HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between MRIs during and after hypothermia (although not significantly); cerebral metabolic rate of oxygen (P=0.93) was not different. Early MRIs were technically feasible while maintaining hypothermic goal temperatures in infants with HIE. Cerebral oxygen metabolism early during hypothermia is more disturbed in severe HIE. In infants with moderate HIE, cerebral blood flow decreased and oxygen extraction fraction increased between early and post-hypothermia scans. A comparison of cerebral oxygen metabolism parameters between early and post-hypothermia MRIs might improve our understanding of the evolution of HIE and the benefits of hypothermia. This approach could guide the use of adjunctive neuroprotective strategies in affected infants.

Background: Moderate to severe hypoxic-ischemic encephalopathy (HIE) in neonates is often treated with hypothermia. However, some neonates may experience epileptic seizures during therapeutic hypothermia (TH). Data on the electrophysiologic and evolutionary aspects of these seizures are scarce in African countries. Objectives: To determine the types of epileptic seizures caused by HIE in neonates in Brazzaville; to describe the evolution of background EEG activities during TH and rewarming; to report the evolution of epileptic seizures. Methods: This was a cross-sectional, descriptive study conducted from January 2020 to July 2022. It took place in Brazzaville in the Neonatology Department of the Blanche Gomez Mother and Child Hospital. It focused on term neonates suffering from moderate or severe HIE. They were treated with hypothermia combined with phenobarbital for 72 hours. Results: Among 36 neonates meeting inclusion criteria, there were 18 boys and 18 girls. Thirty-one (86.1%) neonates had grade 2 and 5 (13.9%) grade 3 HIE. In our neonates, HIE had induced isolated electrographic seizures (n = 11; 30.6%), electroclinical seizures (n = 25; 69.4%), and 6 types of background EEG activity. During TH and rewarming, there were 52.8% of patients with improved background EEG activity, 41.7% of patients with unchanged background EEG activity, and 5.5% of patients with worsened background EEG activity. At the end of rewarming, only 9 (25%) patients still had seizures. Conclusion: Isolated electrographic and electroclinical seizures are the only pathological entities found in our studied population. In neonates with moderate HIE, the applied therapeutic strategy positively influences the evolution of both seizures and background EEG activity. On the other hand, in neonates with severe HIE, the same therapeutic strategy is ineffective.

Hypoxic ischaemic encephalopathy (HIE) is a common cause of neonatal death and severe neurological deficit in children, contributing to medico-legal litigation. To describe the neurodevelopmental outcomes of infants with moderate and severe HIE at Chris Hani Baragwanath Academic Hospital and the proportions with neurodevelopmental impairment (NDI) and complications. To explore the effect of HIE severity and therapeutic hypothermia (TH) on neurodevelopmental outcome. A retrospective, descriptive study at the Neonatal Neurodevelopmental Clinic included 239 infants with moderate and severe HIE, between 2015 and 2020. Neurodevelopmental outcomes were assessed by using the Griffiths Mental Developmental Scales at 1 year. General Quotient (GQ) scores defined NDI. Clinical and investigation criteria determined those with neurological complications. Of the 239 infants, 211 (88.3%) and 28 (11.7%) had moderate HIE and severe HIE, respectively. Cerebral palsy (CP) was diagnosed in 9.2% and NDI in 17.1%. Severe HIE infants had significantly higher rates of NDI and CP, 50% (14) and 21.4% (6) respectively, as compared to those of moderate HIE infants, who had 12.7% (27) NDI and 7.6% (16) CP; 152(72%) moderate and 14 (50%) severe HIE infants received TH. Those who received TH were less likely to have NDI (p = 0.005), CP (p = 0.002), epilepsy and visual impairment. Developmental scores at 1 year of age were in the average range for the cohort, with equivalent profiles across domains. Those with severe HIE had the worst outcomes. Therapeutic hypothermia was associated with decreased CP and NDI in both groups. This report supports the use of TH as a neuroprotective strategy in stage 2 and 3 HIE, highlighting the need for neurodevelopmental assessments at 2 years and beyond to determine longer-term outcomes and subtle deficits.

AimNeonatal Hypoxic Ischemic Encephalopathy (HIE) diagnosis and prognosis are established through clinical evidence, laboratory, imaging, and electrophysiological assessment of the nervous system. Netrin-1 (NT-1) was the first axon guidance molecule...

Hypoxic-ischaemic encephalopathy (HIE) affects 2-4/1000 live term births. Treatment with therapeutic hypothermia (TH) improves the long-term neurodevelopmental outcome of neonates with moderate to severe HIE. However, early prediction of outcome still remains challenging, and no reliable and easily obtainable biomarker has been identified to date. Neonates with HIE display impaired thermoregulation, resulting in spontaneous hypothermia. The degree of cooling required to achieve TH may therefore act as a biomarker of injury severity. The present study demonstrates a correlation between servo-controlled mattress temperature during TH and short-term outcome. Neonates with an unfavourable outcome require less cooling to maintain a core temperature between 33 and 34°C during TH compared to neonates with a favourable outcome. The degree of impaired temperature regulation was strongly associated with a high magnetic resonance imaging injury score and death. Cooling device output temperature is a potential and easily obtainable early physiological biomarker of outcome in infants with HIE undergoing TH. Neonatal hypoxic-ischaemic encephalopathy (HIE) is a leading cause of death and disability in children. Therapeutic hypothermia (TH) at 33.5°C for 72h is the only therapy to date shown to improve outcome in moderate to severe HIE; however, assessment of severity and prediction of outcome remains challenging. Infants with HIE display significant physiological perturbations, including spontaneous hypothermia. We hypothesized that neonates with more severe brain injury on magnetic resonance imaging (MRI) would exhibit a greater degree of spontaneous hypothermia, and thus require less active cooling to attain TH. Twenty-eight neonates with moderate or severe HIE treated with TH were included in the present study. MRI images obtained on day of life 4-7 were scored according to standardized injury criteria. Unfavourable outcome was defined as death or significant grey matter injury on MRI according to a previously validated scoring system. A significantly higher cooling device output temperature was seen in infants with an unfavourable outcome. All neonates who required the mattress to provide a temperature≥32°C to maintain their core body temperature at 33.5°C had a high likelihood of unfavourable outcome (likelihood ratio=14.4).By contrast, infants who never required a device output temperature ≥32°C had a low likelihood of an unfavourable outcome (likelihood ratio=0.07, P<0.001). Infants with significant grey matter injury on MRI require less active cooling to maintain target temperature during TH. The cooling device output temperature has the potential to be an easily accessible physiological biomarker and predictor of injury and mortality in neonates with moderate or severe HIE.

Therapeutic hypothermia (TH) aims to ameliorate further injury in infants with moderate and severe hypoxic ischemic encephalopathy (HIE). We aim to assess the effect of TH on heart rate variability (HRV) in infants with HIE. Multichannel video-electroencephalography (EEG) and electrocardiography were assessed at 6-72 h after birth in full-term infants with HIE, recruited prior to (pre-TH group) and following (TH group) the introduction of TH in our neonatal unit. HIE severity was graded using EEG. HRV features investigated include: mean NN interval (mean NN), standard deviation of NN interval (SDNN), triangular interpolation (TINN), high-frequency (HF), low-frequency (LF), very low-frequency (VLF), and LF/HF ratio. Linear mixed model comparisons were used. 118 infants (pre-TH: n = 44, TH: n = 74) were assessed. The majority of HRV features decreased with increasing EEG grade. Infants with moderate HIE undergoing TH had significantly different HRV features compared with the pre-TH group (HF: P = 0.016, LF/HF ratio: P = 0.006). In the pre-TH group, LF/HF ratio was significantly different between moderate and severe HIE grades (P = 0.002). In the TH group, significant differences were observed between moderate and severe HIE grades for SDNN: P = 0.020, TINN: P = 0.005, VLF: P = 0.029, LF: P = 0.010, and HF: P = 0.006. The HF component of HRV is increased in infants with moderate HIE undergoing TH.

Association between Early Basal Ganglia and Thalami Perfusion Assessed by Color Doppler Ultrasonography and Brain Injury in Infants with Hypoxic-Ischemic Encephalopathy: A Prospective Cohort Study

BackgroundNeonatal hypoxic ischemic encephalopathy (HIE) leads to different degrees of neurological sequelae. The incidence of HIE is relatively high, and the causal pathways leading to HIE are still controversial. This study aimed to investigate the risk factors associated with HIE comparing differences between genders.MethodsA cross-sectional study of 196 neonates diagnosed with HIE was conducted. Based on the severity of clinical findings, HIE was classified as mild, moderate or severe. For mild HIE, the outcomes were relatively less severe, whereas moderate to severe HIE could suffer serious consequences, including death, cerebral palsy, epilepsy. T-test, chi-square test and logistic regression were used to analyze data.ResultsAmong the 196 neonatal HIE, 39 (19.9%) had mild HIE,157 (80.1%) had moderate or severe HIE. The logistic regression analysis showed that gender was a specific stratified characteristic of moderate or severe HIE. In the male neonates group, emergency cesarean section, abnormal labor stage and amniotic fluid contamination were associated with an increased risk of moderate or severe HIE, where the adjusted odds ratios (ORs) were 4.378 (95% confidence intervals (CI):2.263–6.382), 2.827 (95% CI:1.743–5.196) and 2.653 (95%CI:1.645–3.972), respectively. As expected, a significant additive effect was found in the interactions between emergency cesarean section and abnormal labor stage, as well as between emergency cesarean section and amniotic fluid contamination, where the relative excess risk of interaction was 2.315(95%CI:1.573–3.652) and 1.896(95%CI: 1.337–3.861) respectively.ConclusionEmergency cesarean section, abnormal labor stage and amniotic fluid contamination were risk factors of moderate or severe HIE in neonates, and the associations were significantly correlated with male gender. Notably, coinciding incidences of emergency cesarean section with abnormal labor stage, or emergency cesarean section with amniotic fluid contamination were possibly synergistic in increasing the risk of moderate or severe HIE. These findings may assist clinicians in strengthening their awareness on risks affecting HIE and help reduce the incidence of moderate or severe HIE in clinical practice.

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the main causes of neurodevelopmental disorders. We developed a model that has diagnostic and prognostic value in predicting the neurodevelopmental outcomes in newborns with HIE. HIE staging allows us to start therapeutic interventions early in newborns with suspected encephalopathy.&#x0D; Methods: This was a retrospective study in a cohort of 58 full-term neonates with clinical suspicion of HIE. We assessed electroclinical variables at birth [etiology of hypoxia, neonatal seizures, HIE stages based on Sarnat criteria, use of therapeutic hypothermia, neuroimaging tests and electroencephalography (EEG) findings] and two years of follow up (EEG findings, development of epilepsy, the presence of cognitive deficits, behavioral issues, language problems, visual or hearing disturbances, and cerebral palsy).&#x0D; Results: There was a high electro-clinical correlation to severe HIE (88.8%) and moderate HIE (50%). There was a considerable proportion of patients affected by mild HIE, based on clinical examination, who presented with an abnormal EEG (32.3%). There is a relationship between the onset of neonatal seizures, epilepsy, and severe HIE diagnosed with EEG (88.9%). A higher percentage of patients with moderate and severe HIE, based on EEG findings, present abnormal results in cranial ultrasound and cerebral magnetic resonance imaging (62.5%). At two years of age, functional neurodevelopment disturbances were observed most frequently in patients affected with severe and moderate HIE based on EEG.&#x0D; Conclusions: This study shows a model with diagnostic and prognostic value in predicting newborns' neurodevelopmental outcomes with suspected HIE. This knowledge allows us to assess the role of performing serial EEG in patients with suspected HIE and the relevance of EEG findings in the prognosis of neurodevelopmental disorders.

ObjectiveTo analyze the relationship between therapeutic hypothermia (TH) and whole blood high-sensitivity C-reactive protein (hs-CRP) in neonates with hypoxic-ischemic encephalopathy (HIE).MethodRetrospective analysis was made on the clinical data of hospitalized infants diagnosed with asphyxia in our neonatal intensive care unit from January 2014 to June 2021. According to whether TH was performed, they were divided into two groups, the control group (missed the time in other hospitals and did not receive TH) and the treatment group (TH group). In their first ten days, analysis was made on the hs-CRP, white blood cell (WBC) count, neutrophil percentage, platelet count (PLT), and brain MRI. The correlation analysis was carried out based on the severity of brain injury displayed by the brain MRI and the time of hs-CRP elevation to summarize the relationship between TH and the time of hs-CRP elevation and the severity of HIE.Results83 infants were included, 28 in the control group and 55 in the TH group. After birth, 33 infants (60.0%) in the TH group and 2 patients (7.1%) in the control group had elevated hs-CRP, which was statistically significant (P < 0.05). The time window for CRP elevation after TH was 72–96 h after the end of treatment; The results of the brain MRI showed 23 in the TH group and 11in the control group with moderate and severe HIE. 21 infants (all in the TH group) had elevated hs-CRP. MRI showed that the number of infants with mild injury or regular infants whose hs-CRP raised in the TH group was 12, and the rate of hs-CRP elevation was 37.5%; in the control group, the rate was 11.8%. The difference was significant. TH can decrease PLT and WBC, but no significance in the two groups. Blood and sputum cultures were negative in all infants, and there were no signs of infection.ConclusionsTH can increase the blood hs-CRP of HIE neonates, and the probability of its occurrence is related to the severity of HIE. The heavier the HIE, the higher the risk of hs-CRP elevation after TH; The hs-CRP elevation has little to do with infection, and it doesn't recommend using antibiotics actively.

Early diagnosis and outcome prediction of neonatal hypoxic-ischemic encephalopathy with color Doppler ultrasound.

Brain Temperature in Neonates with Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia

To evaluate the association of caffeine with renal and other short-term clinical outcomes in neonates with moderate or severe hypoxic-ischaemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). This retrospective cohort study included neonates born at ≥36 weeks gestational age with moderate or severe HIE treated with TH at our centre between January 2013 and December 2022. In 2019, there was a practice change to administer a single intravenous 20 mg/kg caffeine citrate dose for moderate/severe HIE, forming two cohorts (non-caffeine vs caffeine). The primary outcome was acute kidney injury (AKI), defined by modified Kidney Disease: Improving Global Outcomes criteria. Secondary outcomes included daily serum creatinine, blood-urea nitrogen (BUN), urine output, HIE-pattern lesion on brain-MRI, early EEG background grade, seizures, duration of mechanical ventilation, length of stay, tube-feeding at discharge and in-hospital mortality. 85 neonates met the inclusion criteria; 38 received caffeine, and 47 did not. AKI incidence was lower in the caffeine group (29% vs 47%), although not statistically significant (p=0.09). BUN levels and serum creatinine levels were significantly lower in the caffeine group on days 3-5 (p<0.05). MRI abnormalities consistent with HIE were more frequent in the caffeine group (60% vs 36%, p=0.028), particularly in infants with moderate HIE (p=0.004). EEG background profiles differed, with caffeine-exposed neonates displaying fewer severe (34% vs 65%) and more mild-to-moderate patterns. No significant differences were noted in other secondary outcomes. Caffeine during TH lowered serum creatinine and BUN but did not significantly reduce AKI and was associated with higher rates of MRI lesions. Prospective, dose-controlled trials with pharmacokinetic monitoring and long-term neurodevelopmental follow-up are needed to clarify caffeine's renal benefits and neurological safety in neonatal HIE.

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

Hypoxic-ischemic encephalopathy (HIE) remains a significant cause of mortality and neurodevelopmental impairment despite treatment with therapeutic hypothermia. Magnetic resonance H1-spectroscopy measures concentrations of cerebral metabolites to detect derangements in aerobic metabolism. We assessed MR spectroscopy in neonates with HIE within 18-24h of initiating therapeutic hypothermia and at 5-6 days post therapeutic hypothermia. Eleven neonates with HIE underwent MR spectroscopy of the basal ganglia and white matter. We compared metabolite concentrations during therapeutic hypothermia and post-therapeutic hypothermia and between moderate and severe HIE. During therapeutic hypothermia, neonates with severe HIE had decreased basal ganglia N-acetylaspartate (NAA; 0.62±0.08 vs. 0.72±0.05; P=0.02), NAA + N-acetylaspartylglutamate (NAAG; 0.66±0.11 vs. 0.77±0.06; P=0.05), glycerophosphorylcholine + phosphatidylcholine (GPC+PCh; 0.28±0.05 vs. 0.38±0.06; P=0.02) and decreased white matter GPC+PCh (0.35±0.13 vs. 0.48±0.04; P=0.02) compared to neonates with moderate HIE. For all subjects, basal ganglia NAA decreased (-0.08±0.07; P=0.01), whereas white matter GPC+PCh increased (0.03±0.04; P=0.04) from therapeutic hypothermia MRI to post-therapeutic-hypothermia MRI. All metabolite values are expressed in mmol/L. Decreased NAA and GPC+PCh were associated with greater HIE severity and could distinguish neonates who might benefit most from targeted additional neuroprotective therapies.