Clinical-functional correlation with brain volumetry in severe perinatal asphyxia: a case report.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental. CASE PRESENTATION: A comprehensive analysis of a term infant with perinatal asphyxia using longitudinal 3D brain information from Machine Learning Models is presented. The clinical analysis revealed the perinatal asphyxia diagnosis with APGAR <5 at 5 and 10 minutes, umbilical arterial pH of 7.0 BE of -21.2 mmol / L), neonatal seizures, and invasive ventilation mechanics. Therapeutic interventions: physical, occupational, and language neurodevelopmental therapies. Epilepsy treatment: vagus nerve stimulation, levetiracetam, and phenobarbital. Furthermore, the 3D analysis showed how the volume decreases due to age, exhibiting an increasing asymmetry between hemispheres. The results of the basal ganglia area showed that thalamus asymmetry, caudate, and putamen increase over time while globus pallidus decreases. CLINICAL OUTCOMES: spastic cerebral palsy, microcephaly, treatment-refractory epilepsy. CONCLUSIONS: Slight changes in the basal ganglia and cerebellum require 3D volumetry for detection, as standard MRI examinations cannot fully reveal their complex shape variations. Quantifying these subtle neurodevelopmental changes helps in understanding their clinical implications. Besides, neurophysiological evaluations can boost neuroplasticity in children with neurological sequelae by stimulating new neuronal connections.

Socioemotional and Psychological Outcomes of Hypoxic-Ischemic Encephalopathy: A Systematic Review.

BACKGROUND AND OBJECTIVES: Therapeutic hypothermia has reduced the risk of death or major disability following perinatal hypoxic-ischemic encephalopathy (HIE); however, many children who experience perinatal HIE still go on to develop personal and behavioral challenges, which can be difficult for caregivers and a public health burden for society. Our objective with this review is to systematically identify and synthesize studies that evaluate associations between perinatal HIE and socioemotional or psychological outcomes. METHODS: We screened all search-returned journal articles from Cochrane Library, Embase, Medline, PsycINFO, Scopus, and Web of Science from data inception through February 1, 2023. Keywords related to HIE (eg, neonatal encephalopathy, neonatal brain injury) and outcomes (eg, social*, emotion*, behav* problem, psycholog*, psychiatr*) were searched with a predefined search string. We included all observational human studies reporting socioemotional or psychological sequelae of term HIE. Study data were recorded on standardized sheets, and the Newcastle-Ottawa Scale was adapted to assess study quality. RESULTS: We included 43 studies documenting 3244 HIE participants and 2132 comparison participants. We found statistically significant associations between HIE and social and emotional, behavioral, and psychological and psychiatric deficits throughout infancy, childhood, and adolescence (19 studies). The authors of the included studies also report nonsignificant findings (11 studies) and outcomes without statistical comparison (25 studies). CONCLUSIONS: Perinatal HIE may be a risk factor for a range of socioemotional and psychological challenges in the short- and long-term. Routine screening, early intervention, and follow-up support may be particularly beneficial to this population.

The effect of hypoxic ischemic encephalopathy towards multi-organ complications and its early outcome at a Malaysian district hospital.

INTRODUCTION: Hypoxic ischemic encephalopathy (HIE) is a clinically defined syndrome of disturbed neurologic function in the newborn with evidence of perinatal asphyxia. Stages of HIE are categorised into mild, moderate or severe based on the Sarnat classification. Neurological dysfunction constitutes a part of the wide spectrum of hypoxic ischemic insult as affected infants can have co-existing multi-organ dysfunction which further contributes to morbidities and mortality. This study aims to determine the relationship between the severity of HIE with multi-organ complications and early clinical outcomes. MATERIALS AND METHODS: All neonates who were admitted to the NICU at Hospital Sultan Abdul Halim between January 2018 to December 2022, who fulfilled the inclusion criteria were included. Demographic data, clinical course and investigation results were retrospectively obtained from the medical records. RESULTS: From a total of 90 infants (n = 90) who fulfilled our inclusion criteria, 31 (34%) were mild, 31 (34%) were moderate and 28 (31%) were severe HIE. The mean maternal age was 27 years. Common antenatal issues include diabetes mellitus (37.8%) and anaemia (22.2%). The Apgar scores at 1 and 5 minutes, initial resuscitation requiring intubation, chest compression and adrenaline were associated with higher severity of HIE (p < 0.05). Coagulation dysfunction was the most common complication (79.7%), followed by respiratory dysfunction (33.3%), cardiac dysfunction (28.9%), renal dysfunction (16.1%), haematological dysfunction (15.6%) and hepatic dysfunction (12%). Respiratory and haematological dysfunctions were significantly associated with higher mortality (p < 0.05). There was a significant longer hospital stay (p = 0.023), longer duration of ventilation (p < 0.001) and increase in frequency of seizures (p < 0.001) when comparing moderate and severe HIE patients to mild HIE patients. With increasing severity of HIE, there was also statistically significant higher mortality (p < 0.001). CONCLUSIONS: There is a significant relationship between multiorgan dysfunction, the severity of HIE and mortality. Early anticipation of multi-organ injury is crucial for optimal early management which would reduce the mortality and improve the neurological outcome of the patients.

Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

Factors affecting early childhood growth in hypoxic-ischemic encephalopathy treated with hypothermia.

INTRODUCTION: There is an extensive body of research regarding neurological outcomes following neonatal hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH), with limited data on growth outcomes. We examined perinatal characteristics associated with postnatal growth in this population. METHODS: Convenience cohort of 66 infants with HIE who underwent TH and participated in follow-up at 24 months of age were included. Regression modeling including perinatal anthropomorphics, markers of HIE, and systemic injury was used to evaluate growth at 24 months. RESULTS: Birth head circumference was associated with weight (p = 0.036). MRI severity, pH at admission and birth head circumference were associated with height (p = 0.043, p = 0.015 and p = 0.043 respectively). MRI severity and length of intubation were associated with head circumference (p = 0.038 and p < 0.001 respectively). CONCLUSION: There was a significant association between specific early factors and growth at 24 months among infants with HIE treated with TH.

Desarrollo motor, cognitivo y conductual tras encefalopatía hipóxico-isquémica neonatal / Motor, cognitive and behavioural outcomes after neonatal hypoxic-ischaemic encephalopathy

Introducción: El neurodesarrollo actual de pacientes con encefalopatía hipóxico-isquémica (EHI) neonatal en España se desconoce. Recientes estudios europeos destacan el desplazamiento de la patología grave hacia trastornos motores leves y problemas emocionales. El objetivo de este estudio fue analizar el estado neuroevolutivo integral a los 3años de una cohorte de neonatos con EHI. Pacientes y métodos: Estudio observacional multicéntrico de neonatos ≥35 semanas de edad gestacional con EHI moderada-grave nacidos entre 2011 y 2013 en 12 hospitales de una extensa región española (91.217m2) y ampliado hasta 2017 en el hospital coordinador. Se evaluaron los estudios de neuroimagen neonatal y del neurodesarrollo a los 3años mediante Bayley-III, Peabody Picture Vocabulary Test y Child Behaviour Checklist. Se incluyeron 79 controles sin asfixia perinatal. Resultados: Se reclutaron 63 pacientes, de los cuales 5/63 (7,9%) se excluyeron por presentar otra patología, y 14/58 (24%) fallecieron. De los 44 supervivientes, 42/44 (95,5%) fueron evaluados. De ellos, 10/42 (24%) presentaron evolución adversa (alteraciones visuales o auditivas, epilepsia, parálisis cerebral [PC] o retraso del desarrollo). Adicionalmente se detectaron otras alteraciones: trastorno motor mínimo (TMM) en 6/42 (14%) y más problemas de introversión (10,5% vs 1,3%), ansiedad (34,2% vs 11,7%) y depresión (28,9% vs 7,8%) que los controles (p<0,05). La gravedad de las lesiones en neuroimagen fue significativamente mayor en pacientes con trastorno motor (PC o TMM) (p=0,004) y muerte o evolución adversa (p=0,027). Conclusiones: Además de las secuelas clásicas, el seguimiento de los pacientes con EHI neonatal debería incluir el diagnóstico y el manejo de trastornos motores mínimos y problemas emocionales.(AU)

Introduction: The current neurodevelopmental status of patients with neonatal hypoxic-ischaemic encephalopathy (HIE) in Spain is unknown. Recent European studies highlight a shift of severe pathology towards mild motor disorders and emotional problems. The aim of this study was to analyse neurodevelopmental outcomes in a cohort of neonates with HIE at age 3years. Patients and method: Multicentre observational study of neonates born at 35 or more weeks of gestation with moderate to severe HIE in 2011-2013 in 12 hospitals in a large Spanish region (91,217m2), with the recruitment extended through 2017 in the coordinating hospital. We analysed the findings of neonatal neuroimaging and neurodevelopmental test scores at 3years (Bayley-III, Peabody Picture Vocabulary Test and Child Behavior Checklist). The sample included 79 controls with no history of perinatal asphyxia. Results: Sixty-three patients were recruited, of whom 5 (7.9%) were excluded due to other pathology and 14 (24%) died. Of the 44 survivors, 42 (95.5%) were evaluated. Of these 42, 10 (24%) had adverse outcomes (visual or hearing impairment, epilepsy, cerebral palsy or developmental delay). Other detected problems were minor neurological signs in 6 of the 42 (14%) and a higher incidence of emotional problems compared to controls: introversion (10.5% vs. 1.3%), anxiety (34.2% vs. 11.7%) and depression (28.9% vs. 7.8%) (P<.05). The severity of the lesions on neuroimaging was significantly higher in patients with motor impairment (P=.004) or who died or had an adverse outcome (P=.027). Conclusion: In addition to classical sequelae, the follow-up of patients with neonatal HIE should include the diagnosis and treatment of minor motor disorders and social and emotional problems.(AU)

Risk Factors and Outcomes for Cerebral Palsy With Hypoxic-Ischemic Brain Injury Patterns Without Documented Neonatal Encephalopathy.

BACKGROUND AND OBJECTIVES: Perinatal hypoxic-ischemic brain injury is a leading cause of term-born cerebral palsy, the most common lifelong physical disability. Diagnosis is commonly made in the neonatal period by the combination of neonatal encephalopathy (NE) and typical neuroimaging findings. However, children without a history of neonatal encephalopathy may present later in childhood with motor disability and neuroimaging findings consistent with perinatal hypoxic-ischemic injury. We sought to determine the prevalence of such presentations using the retrospective viewpoint of a large multiregional cerebral palsy registry. METHODS: Patient cases were extracted from the Canadian Cerebral Palsy Registry with gestational age >36 weeks, an MRI pattern consistent with hypoxic-ischemic injury (HII, acute total, partial prolonged, or combined), and an absence of postnatal cause for HII. Documentation of NE was noted. Maternal-fetal risk factors, labor and delivery, neonatal course, and clinical outcome were extracted. Comparisons were performed using χ2 tests and multivariable logistic regression with multiple imputation. Propensity scores were used to assess for bias. RESULTS: Of the 170 children with MRI findings typical for HII, 140 (82.4%, 95% confidence interval [CI] 75.7%-87.7%) had documented NE and 29 (17.0%, 95% CI 11.7%-23.6%) did not. The group without NE had more abnormalities of amniotic fluid volume (odds ratio [OR] 15.8, 95% CI 1.2-835), had fetal growth restriction (OR 4.7, 95% CI 1.0-19.9), had less resuscitation (OR 0.03, 95% CI 0.007-0.08), had higher 5-minute Apgar scores (OR 2.2, 95% CI 1.6-3.0), were less likely to have neonatal seizures (OR 0.004, 95% CI 0.00009-0.03), and did not receive therapeutic hypothermia. MRI was performed at a median 1.1 months (interquartile range [IQR] 0.67-12.8 months) for those with NE and 12.2 months (IQR 6.6-25.9) for those without (p = 0.011). Patterns of injury on MRI were seen in similar proportions. Hemiplegia was more common in those without documented NE (OR 5.1, 95% CI 1.5-16.1); rates of preserved ambulatory function were similar. DISCUSSION: Approximately one-sixth of term-born children with an eventual diagnosis of cerebral palsy and MRI findings consistent with perinatal hypoxic-ischemic brain injury do not have documented neonatal encephalopathy, which was associated with abnormalities of fetal growth and amniotic fluid volume, and a less complex neonatal course. Long-term outcomes seem comparable with their peers with encephalopathy. The absence of documented neonatal encephalopathy does not exclude perinatal hypoxic-ischemic injury, which may have occurred antenatally and must be carefully evaluated with MRI.

Catalpol alleviates hypoxia ischemia-induced brain damage by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis in neonatal rats.

Hypoxic-ischemic encephalopathy (HIE) is a brain damage caused by perinatal hypoxia and blood flow reduction. Severe HIE leads to death. Available treatments remain limited. Oxidative stress and nerve damage are major factors in brain injury caused by HIE. Catalpol, an iridoid glucoside found in the root of Rehmannia glutinosa, has antioxidant and neuroprotective effects. This study examined the neuroprotective effects of catalpol using a neonatal rat HIE model and found that catalpol might protect the brain through inhibiting neuronal ferroptosis and ameliorating oxidative stress. Behavior tests suggested that catalpol treatment improved functions of motor, learning, and memory abilities after hypoxic-ischemic injury. Catalpol treatment inhibited changes to several ferroptosis-related proteins, including p-PI3K, p-AKT, NRF2, GPX4, SLC7A11, SLC3A2, GCLC, and GSS in HIE neonatal rats. Catalpol also prevented changes to several ferroptosis-related proteins in PC12 cells after oxygen-glucose deprivation. The ferroptosis inducer erastin reversed the protective effects of catalpol both in vitro and in vivo. We concluded that catalpol protects against hypoxic-ischemic brain damage (HIBD) by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis.

Early Hyperoxemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy: A Secondary Analysis of the Infant Cooling Evaluation Trial.

OBJECTIVE: To determine the causal relationship between exposure to early hyperoxemia and death or major disability in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns ≥35 weeks' gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 hours of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. RESULTS: Among 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death or major disability. Among hyperoxemic infants (pO2 100-500 mmHg) the proportion with death or major disability was 40/58 (0.69), while the proportion in normoxemic infants (pO2 40-99 mmHg) was 20/48 (0.42). In the adjusted model, hyperoxemia increased the risk of death or major disability (adjusted risk ratio 1.61, 95% CI 1.07-2.00, P = .03) in relation to normoxemia. CONCLUSION: Early hyperoxemia increased the risk of death or major disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

Temporal evolution of electrographic seizures in newborn infants with hypoxic-ischaemic encephalopathy requiring therapeutic hypothermia: a secondary analysis of the ANSeR studies.

BACKGROUND: Despite extensive research on neonatal hypoxic-ischaemic encephalopathy, detailed information about electrographic seizures during active cooling and rewarming of therapeutic hypothermia is sparse. We aimed to describe temporal evolution of seizures and determine whether there is a correlation of seizure evolution with 2-year outcome. METHODS: This secondary analysis included newborn infants recruited from eight European tertiary neonatal intensive care units for two multicentre studies (a randomised controlled trial [NCT02431780] and an observational study [NCT02160171]). Infants were born at 36+0 weeks of gestation with moderate or severe hypoxic-ischaemic encephalopathy and underwent therapeutic hypothermia with prolonged conventional video-electroencephalography (EEG) monitoring for 10 h or longer from the start of rewarming. Seizure burden characteristics were calculated based on electrographic seizures annotations: hourly seizure burden (minutes of seizures within an hour) and total seizure burden (minutes of seizures within the entire recording). We categorised infants into those with electrographic seizures during active cooling only, those with electrographic seizures during cooling and rewarming, and those without seizures. Neurodevelopmental outcomes were determined using the Bayley's Scales of Infant and Toddler Development, Third Edition (BSID-III), the Griffiths Mental Development Scales (GMDS), or neurological assessment. An abnormal outcome was defined as death or neurodisability at 2 years. Neurodisability was defined as a composite score of 85 or less on any subscales for BSID-III, a total score of 87 or less for GMDS, or a diagnosis of cerebral palsy (dyskinetic cerebral palsy, spastic quadriplegia, or mixed motor impairment) or epilepsy. FINDINGS: Of 263 infants recruited between Jan 1, 2011, and Feb 7, 2017, we included 129 infants: 65 had electrographic seizures (43 during active cooling only and 22 during and after active cooling) and 64 had no seizures. Compared with infants with seizures during active cooling only, those with seizures during and after active cooling had a longer seizure period (median 12 h [IQR 3-28] vs 68 h [35-86], p<0·0001), more seizures (median 12 [IQR 5-36] vs 94 [24-134], p<0·0001), and higher total seizure burden (median 69 min [IQR 22-104] vs 167 min [54-275], p=0·0033). Hourly seizure burden peaked at about 20-24 h in both groups, and infants with seizures during and after active cooling had a secondary peak at 85 h of age. When combined, worse EEG background (major abnormalities and inactive background) at 12 h and 24 h were associated with the seizure group: compared with infants with a better EEG background (normal, mild, or moderate abnormalities), infants with a worse EEG background were more likely to have seizures after cooling at 12 h (13 [54%] of 24 vs four [14%] of 28; odds ratio 7·09 [95% CI 1·88-26·77], p=0·0039) and 24 h (14 [56%] of 25 vs seven [18%] of 38; 5·64 [1·81-17·60], p=0·0029). There was a significant relationship between EEG grade at 12 h (four categories) and seizure group (p=0·020). High total seizure burden was associated with increased odds of an abnormal outcome at 2 years of age (odds ratio 1·007 [95% CI 1·000-1·014], p=0·046), with a medium negative correlation between total seizure burden and BSID-III cognitive score (rS=-0·477, p=0·014, n=26). INTERPRETATION: Overall, half of infants with hypoxic-ischaemic encephalopathy had electrographic seizures and a third of those infants had seizures beyond active cooling, with worse outcomes. These results raise the importance of prolonged EEG monitoring of newborn infants with hypoxic-ischaemic encephalopathy not only during active cooling but throughout the rewarming phase and even longer when seizures are detected. FUNDING: Wellcome Trust, Science Foundation Ireland, and the Irish Health Research Board.

Biochemical profiles and organ dysfunction in neonates with hypoxic-ischemic encephalopathy post-hoc analysis of the THIN trial.

BACKGROUND: Therapeutic hypothermia for infants with moderate to severe hypoxic-ischemic encephalopathy is well established as standard of care in high-income countries. Trials from low- and middle-income countries have shown contradictory results, and variations in the level of intensive care provided may partly explain these differences. We wished to evaluate biochemical profiles and clinical markers of organ dysfunction in cooled and non-cooled infants with moderate/severe hypoxic-ischemic encephalopathy. METHODS: This secondary analysis of the THIN (Therapeutic Hypothermia in India) study, a single center randomized controlled trial, included 50 infants with moderate to severe hypoxic-ischemic encephalopathy randomized to therapeutic hypothermia (n = 25) or standard care with normothermia (n = 25) between September 2013 and October 2015. Data were collected prospectively and compared by randomization groups. Main outcomes were metabolic acidosis, coagulopathies, renal function, and supportive treatments during the intervention. RESULTS: Cooled infants had lower pH than non-cooled infants at 6-12 h (median (IQR) 7.28 (7.20-7.32) vs 7.36 (7.31-7.40), respectively, p = 0.003) and 12-24 h (median (IQR) 7.30 (7.24-7.35) vs 7.41 (7.37-7.43), respectively, p < 0.001). Thrombocytopenia (< 100 000) was, though not statistically significant, twice as common in cooled compared to non-cooled infants (4/25 (16%) and 2/25 (8%), respectively, p = 0.67). No significant difference was found in the use of vasopressors (14/25 (56%) and 17/25 (68%), p = 0.38), intravenous bicarbonate (5/25 (20%) and 3/25 (12%), p = 0.70) or treatment with fresh frozen plasma (10/25 (40%) and 8/25 (32%), p = 0.56)) in cooled and non-cooled infants, respectively. Urine output < 1 ml/kg/h was less common in cooled infants compared to non-cooled infants at 0-24 h (7/25 (28%) vs. 16/23 (70%) respectively, p = 0.004). CONCLUSIONS: This post hoc analysis of the THIN study support that cooling of infants with hypoxic-ischemic encephalopathy in a level III neonatal intensive care unit in India was safe. Cooled infants had slightly lower pH, but better renal function during the first day compared to non-cooled infants. More research is needed to identify the necessary level of intensive care during cooling to guide further implementation of this neuroprotective treatment in low-resource settings. TRIAL REGISTRATION: Data from this article was collected during the THIN-study (Therapeutic Hypothermia in India; ref. CTRI/2013/05/003693 Clinical Trials Registry - India).

Frequency of Cerebellar Abnormalities Associated With the Differing Magnetic Resonance Imaging Patterns of Term Hypoxic-Ischemic Injury in Children.

BACKGROUND: We aimed to determine the frequency of cerebellar injury using delayed magnetic resonance imaging (MRI) in children with cerebral palsy, diagnosed with term hypoxic-ischemic injury (HII), and to characterize this for the different MRI patterns of HII. METHODS: We retrospectively reviewed delayed MRI scans in children with cerebral palsy, of whom 1175 had term HII. The pattern of HII was classified into basal ganglia-thalamus (BGT) pattern, watershed (WS) pattern, combined BGT/WS, and multicystic HII. Cerebellar location (hemisphere versus vermis) and the MRI characteristics were documented overall and for each of the different patterns of HII, as well as the association with thalamic injury. RESULTS: Cerebellar injury was found in 252 of 1175 (21.4%) (median age 6 years [interquartile range: 3 to 9 years]). Of these, 49% (124 of 252) were associated with a BGT pattern, 13% (32 of 252) with a WS pattern, 28% (72 of 252) with a combined BGT/WS pattern, and 10% (24 of 252) with a multicystic pattern. The vermis was abnormal in 83% (209 of 252), and the hemispheres were abnormal in 34% (86 of 252) (with 17% [43 of 252] showing both vermis and hemispheric abnormality). CONCLUSIONS: Over a fifth of patients with cerebral palsy due to HII had a cerebellar abnormality on delayed MRI, most commonly involving the vermis (83%), and as part of a BGT pattern of injury in just under half of these likely reflecting the association of cerebellar vermis injury with profound insults.

Monitoring of Brain Tissue Oxygen Tension in Cardiac Arrest: a Translational Systematic Review from Experimental to Clinical Evidence.

BACKGROUND: Cardiac arrest (CA) is a sudden event that is often characterized by hypoxic-ischemic brain injury (HIBI), leading to significant mortality and long-term disability. Brain tissue oxygenation (PbtO2) is an invasive tool for monitoring brain oxygen tension, but it is not routinely used in patients with CA because of the invasiveness and the absence of high-quality data on its effect on outcome. We conducted a systematic review of experimental and clinical evidence to understand the role of PbtO2 in monitoring brain oxygenation in HIBI after CA and the effect of targeted PbtO2 therapy on outcomes. METHODS: The search was conducted using four search engines (PubMed, Scopus, Embase, and Cochrane), using the Boolean operator to combine mesh terms such as PbtO2, CA, and HIBI. RESULTS: Among 1,077 records, 22 studies were included (16 experimental studies and six clinical studies). In experimental studies, PbtO2 was mainly adopted to assess the impact of gas exchanges, drugs, or systemic maneuvers on brain oxygenation. In human studies, PbtO2 was rarely used to monitor the brain oxygen tension in patients with CA and HIBI. PbtO2 values had no clear association with patients' outcomes, but in the experimental studies, brain tissue hypoxia was associated with increased inflammation and neuronal damage. CONCLUSIONS: Further studies are needed to validate the effect and the threshold of PbtO2 associated with outcome in patients with CA, as well as to understand the physiological mechanisms influencing PbtO2 induced by gas exchanges, drug administration, and changes in body positioning after CA.

Seizures after initiation of rewarming in cooled infants with hypoxic ischaemic encephalopathy.

BACKGROUND: Seizures after initiation of rewarming from therapeutic hypothermia for neonatal encephalopathy are well recognised but not easy to predict. METHODS: A secondary analysis was performed of NEOLEV2 trial data, a multicentre randomised trial of levetiracetam versus phenobarbital for neonatal seizures. Enrolled infants underwent continuous video EEG (cEEG) monitoring. The trial data were reviewed for 42 infants with seizures during therapeutic hypothermia and 118 infants who received therapeutic hypothermia but had no seizures on cEEG. RESULTS: Overall, 112 of 160 (70%) had cEEG monitoring continued until rewarming was completed. Of the 42 infants with prior seizures, there were 30 infants with valid cEEG available and seizures occurred following the initiation of rewarming in 8 (26.6%). For the 118 seizure-naive infants, 82 (69.5%) continued cEEG until either rewarming was completed or 90 h of age and none had documented seizures. CONCLUSION: Overall, just over a quarter of infants with prior seizures had cEEG evidence of at least one seizure in the 24 h after initiation of rewarming but no seizure-naive infant had cEEG evidence of seizure(s) on rewarming. Critically, by reporting the two groups separately, the data can provide guidance on the duration of EEG monitoring. IMPACT: Infants with hypoxic ischaemic encephalopathy who have cEEG evidence of seizures during therapeutic hypothermia have a significant risk of further seizures on rewarming. For infants with hypoxic ischaemic encephalopathy but no cEEG evidence of seizures during therapeutic hypothermia, there is very little risk of de novo seizures. Ongoing work utilising large cohorts may generate EEG criteria that refine estimates of risk for rewarming seizures. Based on current experience, if seizures have occurred during therapeutic hypothermia for hypoxic ischaemic encephalopathy, the EEG monitoring should be continued during rewarming and for 12 h thereafter to minimise the risk of missing an event.

A predictive model for perinatal hypoxic ischemic encephalopathy using linked maternal and neonatal hospital data.

PURPOSE: To build an evidence-based model to estimate case-specific risk of perinatal hypoxic ischemic encephalopathy. METHODS: A retrospective, cross-sectional study of all births in Hawaii, Michigan, and New Jersey between 2010 and 2015, using linked maternal labor/delivery and neonatal birth records. Stepwise logistic regression and competitive Akaike information criterion were used to identify the most parsimonious model. Predictive ability of the model was measured with bootstrapped optimism-adjusted area under the ROC curve. RESULTS: Among 836,216 births there were 376 (0.45 per 1000) cases of hypoxic ischemic encephalopathy. The final model included 28 variables, 24 associated with increased risk, and 4 that were protective. The optimism-adjusted area under the ROC curve was 0.84. Estimated risk in the study population ranged from 1 in ∼323,000 to 1 in 2.5. The final model confirmed known risk factors (e.g., sentinel events and shoulder dystocia) and identified novel risk factors, such as maternal race and insurance status. CONCLUSION: Our study shows that risk of perinatal hypoxic ischemic encephalopathy injury can be estimated with high confidence. Our model fills a notable gap in the study of hypoxic ischemic encephalopathy prevention: the estimation of risk, particularly in the United States population which is unique with respect to racial and socioeconomic disparities.

Acute kidney injury in infants with hypoxic-ischemic encephalopathy.

BACKGROUND: This study aimed to investigate the prevalence of acute kidney injury (AKI) in infants with varying degrees of hypoxic-ischemic encephalopathy (HIE) and its associated outcomes, including mortality and length of stay (LOS). METHODS: The study used the National Inpatient Sample (NIS) dataset from 2010 to 2018. Regression analysis was used to control confounding variables. RESULTS: Of 31,220,784 infants included in the study, 30,130 (0.1%) had HIE. The prevalence of AKI was significantly higher in infants with HIE (9.0%) compared to those without (0.04%), with an adjusted odds ratio (aOR) of 77.6 (CI:70.1-85.7, p < 0.001), with the highest prevalence of AKI in infants with severe HIE (19.7%), aOR:130 (CI: 107-159), p < 0.001). Infants with AKI had a higher mortality rate compared to those without AKI in those diagnosed with any degree of HIE (28.9% vs. 8.8%), aOR 3.5 (CI: 3.2-3.9, p < 0.001), particularly among those with severe HIE, aOR:1.4 (1.2-1.6, p < 0.001). CONCLUSIONS: HIE is associated with an increased prevalence of AKI. Infants with severe HIE had the highest prevalence of AKI and associated mortality. The study highlights the need for close monitoring and early detection of AKI in infants with HIE, particularly those with severe HIE, to ameliorate the associated adverse outcomes.

Simple approach to quantify hypoxic-ischemic brain injury severity from computed tomography imaging files after cardiac arrest.

BACKGROUND: Grey-white ratio (GWR) can estimate severity of cytotoxic cerebral edema secondary to hypoxic-ischemic brain injury after cardiac arrest and predict progression to death by neurologic criteria (DNC). Current approaches to calculating GWR are not standardized and have variable interrater reliability. We tested if measures of variance of brain density on early computed tomographic (CT) imaging after cardiac arrest could predict DNC. METHODS: We performed a retrospective cohort study, identifying post-arrest patients treated between 2011 and 2020 at our single center. We extracted demographic data from our registry and Digital Imaging and Communication in Medicine (DICOM) files for each patient's first brain CT. We analyzed slices 15-20 of each DICOM, corresponding to the level of the basal ganglia while accommodating differences in patient anatomy. We extracted pixel arrays and converted the radiodensities to Hounsfield units (HU). To focus on brain tissue densities, we excluded HU > 60 and < 10. We calculated the variance of each patient's HU distribution and the difference between the means of a two-group Gaussian finite mixture model. We compared these novel metrics to existing measures of cerebral edema, then randomly divided our data into 80% training and 20% test sets and used logistic regression to predict DNC. RESULTS: Of 1,133 included subjects, 457 (40%) were female, mean (standard deviation) age was 58 (16) years, and 115 (10%) progressed to DNC. CTs were obtained a median [interquartile range] of 4.2 [2.8-5.7] hours post-arrest. Our novel measures correlated weakly with GWR. HU variance, but not difference between mixture model means, differed significantly between subjects with and without sulcal or cistern effacement. GWR outperformed our novel measures in predicting progression to DNC with an area under the receiver operating characteristic curve (AUC) of 0.82, compared to HU variance (AUC = 0.73) and the difference between mixture model means (AUC = 0.56). CONCLUSION: There are differences in the distribution of HU on post-arrest CT in patients with qualitative measures of cerebral edema. Current methods to quantify cerebral edema outperform simple measures of attenuation variance on early brain CT. Further analyses could investigate if these measures of variance, or other distributional characteristics of brain density, have improved predictive performance on brain CTs obtained later in the clinical course or derived from discrete regions of anatomical interest.

Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2. RESULTS: Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI, -6.1 to 0.5], language -3.3 [95% CI, -7.4 to 0.8], and motor -3.5 [95% CI, -7.3 to 0.3]). CONCLUSIONS: In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age. TRIAL REGISTRATION: High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta. CLINICALTRIALS: gov/study/NCT02811263.

A New Approach for Exploring Reperfusion Brain Damage in Hypoxic Ischemic Encephalopathy.

Reperfusion is an essential pathological stage in hypoxic ischemic encephalopathy (HIE). Although the Rice-Vannucci model is widely used in HIE research, it remains difficult to replicate HIE-related reperfusion brain injury. The purpose of this study is to establish a rat model of hypoxia ischemia reperfusion brain damage (HIRBD) using a common carotid artery (CCA) muscle bridge in order to investigate the mechanisms of cerebral resistance to hypoxic-ischemic and reperfusion brain damage. Random assignment of Sprague-Dawley (SD) rats to the Sham, HIRBD, and Rice-Vannucci groups. Changes in body weight, mortality rate, spontaneous alternation behavior test (SAB test), and dynamic changes in cerebral blood flow (CBF) were detected. The damaged cerebral cortices were extracted for morphological comparison, transcriptomic analysis, and quantitative real-time PCR. Harvesting the hippocampus for transmission electron microscopy (TEM) detection. As a result, CCA muscle bridge could effectively block CBF, which recovered after the muscle bridge detachment. Pathological comparison, the SAB test, and TEM analysis revealed that brain damage in Rice-Vannucci was more severe than HIRBD. Gpx1, S100a6, Cldn5, Esr1, and Gfap were highly expressed in both HIRBD and Rice-Vannucci. In conclusion, the CCA muscle bridge-established HIRBD model could be used as an innovative and dependable model to simulate pathological process of HIRBD.