Hypoxic-ischaemic encephalopathy code: A systematic review for resource-limited settings.

It is estimated that 96% of infants with hypoxic-ischaemic encephalopathy (HIE) are born in resource-limited settings with no capacity to provide the standard of care that has been established for nearly 15 years in high-resource countries, which includes therapeutic hypothermia (TH), continuous electroencephalographic monitoring and magnetic resonance imaging (MRI) in addition to close vital signs and haemodynamic monitoring. This situation does not seem to be changing; however, even with these limitations, currently available knowledge can help improve the care of HIE patients in resource-limited settings. The purpose of this systematic review was to provide, under the term "HIE Code", evidence-based recommendations for feasible care practices to optimise the care of infants with HIE and potentially help reduce the risks associated with comorbidity and improve neurodevelopmental outcomes. The content of the HIE code was grouped under 9 headings: (1) prevention of HIE, (2) resuscitation, (3) first 6h post birth, (4) identification and grading of encephalopathy, (5) seizure management, (6) other therapeutic interventions, (7) multiple organ dysfunction, (8) diagnostic tests and (9) family care.

General movement assessment efficacy for assessment of nervous system integrity in children after hypoxic-ischemic encephalopathy in middle income countries.

BACKGROUND: Many infants who survive hypoxic-ischemic encephalopathy (HIE) face long-term complications like epilepsy, cerebral palsy, and developmental delays. Detecting and forecasting developmental issues in high-risk infants is critical. AIM: This study aims to assess the effectiveness of standardized General Movements Assessment (GMA) and Hammersmith Infant Neurological Examinations (HINE) in identifying nervous system damage and predicting neurological outcomes in infants with HIE. DESIGN: Prospective. SUBJECTS AND MEASURES: We examined full-term newborns with perinatal asphyxia, classifying them as Grade 2 HIE according to Sarnat and Sarnat. The study included 31 infants, with 14 (45.2 %) receiving therapeutic hypothermia (Group 1) and 17 (54.8 %) not (Group 2). We evaluated general movements during writhing and fidgety phases and conducted neurological assessments using the HINE. RESULTS: All infants exhibited cramped-synchronized - like movements, leading to cerebral palsy (CP) diagnosis. Three children in Group 1 and four in Group 2 lacked fidgety movements. During active movements, HINE and GMA showed high sensitivity and specificity, reaching 96 % and 100 % for all children. The ROC curve's area under the curve (AUC) was 0.978. CONCLUSION: Our study affirms HINE and GMA as effective tools for predicting CP in HIE-affected children. GMA exhibits higher sensitivity and specificity during fidgety movements. However, study limitations include a small sample size and data from a single medical institution, necessitating further research.

Identifying Newborns with Hypoxic-Ischemic Encephalopathy in Hospital Discharge Data: A Validation Study.

Hospital discharge databases (HDDs) are increasingly used for research on health of newborns. Linkage between a French population-based cohort of newborns with hypoxic-ischemic encephalopathy (HIE) and national HDD showed that the HIE ICD-10 code was not accurately reported. Our results suggest that HDD should not be used for research on neonatal HIE without prior validation of HIE ICD-10 codes.

Epilepsy Incidence and Developmental Outcomes After Early Discontinuation of Antiseizure Medication in Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Neonatal seizures caused by hypoxic-ischemic encephalopathy (HIE) have significant morbidity and mortality. There is variability in clinical practice regarding treatment duration with antiseizure medication (ASM) after resolution of provoked neonatal seizures. We examined epilepsy incidence and developmental outcomes in post-HIE neonates discharged or not on ASM. METHODS: We conducted a retrospective chart review of all HIE-admitted neonates to the University of Iowa Hospitals & Clinics neonatal intensive care unit between January 2008 and February 2021 who presented with encephalopathy, underwent therapeutic hypothermia, and developed seizures. Neonates were divided into two groups depending on whether ASM was continued or discontinued on discharge. We evaluated the incidence of epilepsy and developmental outcomes on follow-up in these two cohorts up to 12 months. RESULTS: Sixty-nine neonates met the study criteria. ASM was continued on discharge in 41 neonates (59%) and discontinued before discharge in 28 (41%). At the 12-month follow-up, nine neonates (13%) had a diagnosis of epilepsy, out of which seven neonates had ASM continued on discharge (odds ratio [OR]: 2.84; 95% confidence interval [CI]: 0.48, 29.9)]. There was no statistical difference between the development of postneonatal epilepsy between the two groups (P value 0.29). There was no significant difference in developmental outcome between the two groups after adjusting for covariates like magnetic resonance imaging (MRI) brain abnormality and number of seizure days (OR: 0.68; 95% CI: 0.21, 2.22; P = 0.52). CONCLUSION: We found no significant risk of seizure recurrence by age 12 months in infants who had discontinued ASM before discharge compared with those who had continued ASM. There was no difference in developmental outcomes at the 12-month follow-up between groups after adjusting for brain MRI abnormality and the number of seizure days during admission. Our results support early discontinuation of ASM after resolution of acute provoked seizures in neonates with HIE.

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)

Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 µg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Detailed statistical analysis plan for ALBINO: effect of Allopurinol in addition to hypothermia for hypoxic-ischemic Brain Injury on Neurocognitive Outcome - a blinded randomized placebo-controlled parallel group multicenter trial for superiority (phase III).

BACKGROUND: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45-50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol - a xanthine oxidase inhibitor - reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. METHODS/DESIGN: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. RESULTS: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and ."will be stratified for the two treatment groups. DISCUSSION: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017.

Hypoxic Ischemic Encephalopathy with Cervical Spinal Cord Injury: A Diagnostic Dilemma.

Perinatal spinal cord injury is a relatively uncommon, but a frequently misdiagnosed disorder. Improvements in obstetric care have certainly led to a decrease in the incidence of birth related spinal cord trauma but unfortunately the incidence of hypoxic-ischemic encephalopathy is still very high. The exact incidence of spinal cord trauma is difficult to determine because the spinal cord is not routinely examined in far and few neonatal autopsies done in India. Here, authors present a neonate who received treatment for birth asphyxia and then had extubation failure which made the clock tick towards cervical cord injury. This baby had a hemorrhagic contusion of cervical spinal cord.

Evaluating Injury Severity in Neonatal Encephalopathy Using Automated Quantitative Electroencephalography Analysis: A Pilot Study.

Quantitative analysis of electroencephalography (qEEG) is a potential source of biomarkers for neonatal encephalopathy (NE). However, prior studies using qEEG in NE were limited in their generalizability due to individualized techniques for calculating qEEG features or labor-intensive pre-selection of EEG data. We piloted a fully automated method using commercially available software to calculate the suppression ratio (SR), absolute delta power, and relative delta, theta, alpha, and beta power from EEG of neonates undergoing 72 h of therapeutic hypothermia (TH) for NE between April 20, 2018, and November 4, 2019. We investigated the association of qEEG with degree of encephalopathy (modified Sarnat score), severity of neuroimaging abnormalities following TH (National Institutes of Child Health and Development Neonatal Research Network [NICHD-NRN] score), and presence of seizures. Thirty out of 38 patients met inclusion criteria. A more severe modified Sarnat score was associated with higher SR during all phases of TH, lower absolute delta power during all phases except rewarming, and lower relative delta power during the last 24 h of TH. In 21 patients with neuroimaging data, a worse NICHD-NRN score was associated with higher SR, lower absolute delta power, and higher relative beta power during all phases. QEEG features were not significantly associated with the presence of seizures after correction for multiple comparisons. Our results are consistent with those of prior studies using qEEG in NE and support automated qEEG analysis as an accessible, generalizable method for generating biomarkers of NE and response to TH. Additionally, we found evidence of an immature relative frequency composition in neonates with more severe brain injury, suggesting that automated qEEG analysis may have a use in the assessment of brain maturity.

A comparative proteomic analysis for non-invasive early prediction of hypoxic-ischemic injury in asphyxiated neonates.

AIM: Hypoxic Ischemic Encephalopathy (HIE) is one of the principal causes of neonatal mortality and long-term morbidity worldwide. The neonatal signs of mild cerebral injury are subtle, making an early precise diagnosis difficult. Delayed detection, poor prognosis, and lack of specific biomarkers for the disease are increasing mortality rates. In this study, we intended to identify specific biomarkers using comparative proteomic analysis to predict the severity of perinatal asphyxia so that its outcome can also be prevented. EXPERIMENTAL DESIGN: A case-control study was conducted on 38 neonates, and urine samples were collected within 24 and 72 h of life. A tandem mass spectrometry-based quantitative proteomics approach, followed by validation via sandwich ELISA, was performed. RESULTS: The LC-MS/MS-based proteomics analysis resulted in the identification of 1201 proteins in urine, with 229, 244, and 426 being differentially expressed in HIE-1, HIE-2, and HIE-3, respectively. Axon guidance, Diseases of programmed cell death, and Detoxification of reactive oxygen species pathways were significantly enriched in mild HIE versus severe HIE. Among the differentially expressed proteins in various stages of HIE, we chose to validate four proteins - APP, AGT, FABP1, and FN1 - via sandwich ELISA. Individual and cumulative ROC curves were plotted. AGT and FABP1 together showed high sensitivity, specificity, and accuracy as potential biomarkers for early diagnosis of HIE. CONCLUSION: Establishing putative urinary biomarkers will facilitate clinicians to more accurately screen neonates for brain injury and monitor the disease progression. Prompt treatment of neonates may reduce mortality and neurodevelopmental impairment.

The Association of Therapeutic Hypothermia With Seizure Burden in Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To compare seizure burden between newborn infants treated with therapeutic hypothermia (TH) and those that were not and to compare the need for antiseizure medications (ASM) in a cohort of infants who were diagnosed with neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: This was a retrospective cohort study on infants born after 35 weeks' gestation, diagnosed with moderate to severe HIE, monitored with amplitude-integrated electroencephalography (aEEG) and eligible for TH. Infants born before the implementation of TH in 2008 were compared with infants born thereafter who received TH. Seizure burden was assessed from aEEG as total time in minutes of seizures activity per hour of recording. Other clinical and demographic data were retrieved from a prospective local database of infants with HIE. RESULTS: Overall, 149 of 207 infants were included in the study: 112 exposed to TH and 37 not exposed. Cooled infants had a lower seizure burden overall (0.4 vs 2.3 min/h, P < 0.001) and were also less likely to be treated with ASM (74% vs 100%, P < 0.001). In multivariable regression models, not exposed to TH, having a depressed aEEG background, and having higher Apgar scores were associated with higher seizure burden (incidence rate ratio: 4.78 for noncooled infants, P < 0.001); also, not exposed to TH was associated with a higher likelihood of multidrug ASM (odds ratio: 4.83, P < 0.001). CONCLUSIONS: TH in infants with moderate to severe HIE is associated with significant reduction of seizure burden and ASM therapy.

The influence of late prematurity on the encephalopathy exam of infants with neonatal encephalopathy.

BACKGROUND: Late preterm (LPT) infants are increasingly treated for hypoxic-ischemic encephalopathy (HIE). However, neurodevelopmental differences of LPT infants may independently influence the neurologic exam and confound care. METHODS: Perinatal and outcome characteristics were extracted along with the worst autonomic and state/neuromuscular/reflex Sarnat components in a cross-section of infants with moderate/severe HIE. Infants were classified as late preterm (LPT, 34-36 weeks) or term (>36 weeks). RESULTS: 250 infants were identified, 55 were late preterm. LPT infants had lower mean gestational age and birthweight and greater length of stay (LOS). LPT infants had higher median scores for the Moro and respiratory autonomic components, but no difference in total score. CONCLUSIONS: LPT infants had increased LOS, worse Moro reflex, and respiratory status, but no clinically or statistically significant differences in total Sarnat scores. Although it is important to note the impact of immaturity on the exam, it is unlikely to independently alter management.

Timely Detection of Infants at Risk of Intrapartum Acidosis and Hypoxic-Ischemic Encephalopathy Using Cardiotocography.

This work aims to improve the intrapartum detection of fetuses with an increased risk of developing fetal acidosis or hypoxic-ischemic encephalopathy (HIE) using fetal heart rate (FHR) and uterine pressure (UP) signals. Our study population comprised 40,831 term births divided into 3 classes based on umbilical cord or early neonatal blood gas assessments: 374 with verified HIE, 3,047 with acidosis but no encephalopathy and 37,410 healthy babies with normal gases. We developed an intervention recommendation system based on a random forest classifier. The classifier was trained using classical and novel features extracted electronically from 20-minute epochs of FHR and UP. Then, using the predictions of the classifier on each epoch, we designed a decision rule to determine when to recommended intervention. Compared to the Caesarean rates in each study group, our system identified an additional 5.68% of babies who developed HIE (54.55% vs 60.23%, p < 0.01) with a specific alert threshold. Importantly, about 75% of these recommendations were made more than 200 minutes before birth. In the acidosis group, the system identified an additional 17.44% (37.15% vs 54.59%, p < 0.01) and about 2/3 of these recommendations were made more than 200 minutes before birth. Compared to the Caesarean rate in the healthy group, the associated false positive rate was increased by 1.07% (38.80% vs 39.87%, p<0.01).Clinical Relevance- This method recommended intervention in more babies affected by acidosis or HIE, than the intervention rate observed in practice and most often did so 200 minutes before delivery. This was early enough to expect that interventions would have clinical benefit and reduce the rate of HIE. Given the high burden associated with HIE, this would justify the marginal increase in the normal Cesarean rate.

Growth and developmental outcomes of infants with hypoxic ischemic encephalopathy.

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed.

The Placenta and Neonatal Encephalopathy with a Focus on Hypoxic-Ischemic Encephalopathy.

Background: Placental examination is important for its diagnostic immediacy to correlate with maternal and/or fetal complications and parturitional difficulties. In a broader context, clinicopathologic studies of the placenta have addressed a range of pathogenetic questions that have led to conclusive and inconclusive results and interpretations. Methods: Recent standardized morphologic criteria and terminology of placental lesions have facilitated the ability to compare findings from studies that have focused on complications and outcomes of pregnancy. This review is an evaluation of recent studies on placental lesions associated with hypoxic-ischemic encephalopathy (HIE). Conclusion: No apparent consensus exists on whether it is fetal inflammation with the release of cytokines or chronic maternal and/or fetal vascular malperfusion is responsible for HIE with a lowering of the threshold for hypoxic ischemia. The counter argument is that HIE occurs solely as an intrapartum event. Additional investigation is necessary.

Clinical Prediction Models and Predictors for Death or Adverse Neurodevelopmental Outcome in Term Newborns with Hypoxic-Ischemic Encephalopathy: A Systematic Review of the Literature.

BACKGROUND: Although many predictive parameters have been studied, an internationally accepted, validated predictive model to predict the clinical outcome of asphyxiated infants suffering from hypoxic-ischemic encephalopathy is currently lacking. The aim of this study was to identify, appraise and summarize available clinical prediction models, and provide an overview of all investigated predictors for the outcome death or neurodevelopmental impairment in this population. METHODS: A systematic literature search was performed in Medline and Embase. Two reviewers independently included eligible studies and extracted data. The quality was assessed using PROBAST for prediction model studies and QUIPS assessment tools for predictor studies. RESULTS: A total of nine prediction models were included. These models were very heterogeneous in number of predictors assessed, methods of model derivation, and primary outcomes. All studies had a high risk of bias following the PROBAST assessment and low applicability due to complex model presentation. A total of 104 predictor studies were included investigating various predictors, showing tremendous heterogeneity in investigated predictors, timing of predictors, primary outcomes, results, and methodological quality according to QUIPS. Selected high-quality studies with accurate discriminating performance provide clinicians and researchers an evidence map of predictors for prognostication after HIE in newborns. CONCLUSION: Given the low methodological quality of the currently published clinical prediction models, implementation into clinical practice is not yet possible. Therefore, there is an urgent need to develop a prediction model which complies with the PROBAST guideline. An overview of potential predictors to include in a prediction model is presented.

Association of cerebral metabolic rate following therapeutic hypothermia with 18-month neurodevelopmental outcomes after neonatal hypoxic ischemic encephalopathy.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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 >85 at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (ß (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10 moL/dl × mm2/s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes. INTERPRETATION: 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. FUNDING: 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).

Value of EEG in outcome prediction of hypoxic-ischemic brain injury in the ICU: A narrative review.

Prognostication of comatose patients after cardiac arrest aims to identify patients with a large probability of favourable or unfavouble outcome, usually within the first week after the event. Electroencephalography (EEG) is a technique that is increasingly used for this purpose and has many advantages, such as its non-invasive nature and the possibility to monitor the evolution of brain function over time. At the same time, use of EEG in a critical care environment faces a number of challenges. This narrative review describes the current role and future applications of EEG for outcome prediction of comatose patients with postanoxic encephalopathy.

Characteristics, Genetic Testing, and Diagnoses of Infants with Neonatal Encephalopathy Not Due to Hypoxic Ischemic Encephalopathy: A Cohort Study.

OBJECTIVE: To characterize the presentation and evaluation of infants with neonatal encephalopathy (NE) not due to hypoxic-ischemic encephalopathy (non-HIE NE) and to describe the genetic abnormalities identified. STUDY DESIGN: Retrospective cohort study of 193 non-HIE NE neonates admitted to a level IV NICU from 2015 through 2019. For changes in testing over time, Cochrane-Armitage test for trend was used with a Bonferroni-corrected P-value, and comparison between groups was performed using Fisher exact test. RESULT: The most common symptom of non-HIE NE was abnormal tone in 47% (90/193). Ten percent (19/193) died prior to discharge, and 48% of survivors (83/174) required medical equipment at discharge. Forty percent (77/193) underwent genetic testing as an inpatient. Of 52 chromosomal studies, 54 targeted tests, and 16 exome sequences, 10%, 41%, and 69% were diagnostic, respectively, with no difference in diagnostic rates between infants with and without an associated congenital anomaly and/or dysmorphic feature. Twenty-eight genetic diagnoses were identified. CONCLUSIONS: Neonates with non-HIE NE have high rates of morbidity and mortality and may benefit from early genetic testing, even in the absence of other exam findings. This study broadens our knowledge of genetic conditions underlying non-HIE NE, which may enable families and care teams to anticipate the needs of the individual, allow early initiation of targeted therapies, and facilitate decisions surrounding goals of care.