Impact of persistent pulmonary hypertension and oxygenation on brain injury in neonates with neonatal encephalopathy treated with therapeutic hypothermia.

OBJECTIVE: To investigate the effects of persistent pulmonary hypertension (PPHN) and oxygenation on outcome of neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). STUDY DESIGN: We compared the outcome of neonates with NE treated with TH with or without PPHN. RESULTS: 384 neonates with NE were treated with TH; 24% had PPHN. The fraction of inspired oxygen was higher in the first 4 days of life (p < 0.001) in neonates with PPHN. They had a significantly lower arterial partial pressure of oxygen in the first 4 days of life (p = 0.005) and higher on days 3-4 of life (p < 0.001). They were more often intubated (p < 0.001) and more often had concomitant hypotension (p < 0.001). They had higher mortality (p = 0.009) and more often developed brain injury (p = 0.02). CONCLUSION: PPHN occurred frequently in neonates with NE treated with TH and was associated with a higher incidence of adverse outcome.

Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series).

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

Feasibility and Safety of Sildenafil to Repair Brain Injury Secondary to Birth Asphyxia (SANE-01): A Randomized, Double-blind, Placebo-controlled Phase Ib Clinical Trial.

OBJECTIVE: To test feasibility and safety of administering sildenafil in neonates with neonatal encephalopathy (NE), developing brain injury despite therapeutic hypothermia (TH). STUDY DESIGN: We performed a randomized, double-blind, placebo-controlled phase Ib clinical trial between 2016 and 2019 in neonates with moderate or severe NE, displaying brain injury on day-2 magnetic resonance imaging (MRI) despite TH. Neonates were randomized (2:1) to 7-day sildenafil or placebo (2 mg/kg/dose enterally every 12 hours, 14 doses). Outcomes included feasibility and safety (primary outcomes), pharmacokinetics (secondary), and day-30 neuroimaging and 18-month neurodevelopment assessments (exploratory). RESULTS: Of the 24 enrolled neonates, 8 were randomized to sildenafil and 3 to placebo. A mild decrease in blood pressure was reported in 2 of the 8 neonates after initial dose, but not with subsequent doses. Sildenafil plasma steady-state concentration was rapidly reached, but decreased after TH discontinuation. Twelve percent of neonates (1/8) neonates died in the sildenafil group and 0% (0/3) in the placebo group. Among surviving neonates, partial recovery of injury, fewer cystic lesions, and less brain volume loss on day-30 magnetic resonance imaging were noted in 71% (5/7) of the sildenafil group and in 0% (0/3) of the placebo group. The rate of death or survival to 18 months with severe neurodevelopmental impairment was 57% (4/7) in the sildenafil group and 100% (3/3) in the placebo group. CONCLUSIONS: Sildenafil was safe and well-absorbed in neonates with NE treated with TH. Optimal dosing needs to be established. Evaluation of a larger number of neonates through subsequent phases II and III trials is required to establish efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.govNCT02812433.

A Population Model of Time-Dependent Changes in Serum Creatinine in (Near)term Neonates with Hypoxic-Ischemic Encephalopathy During and After Therapeutic Hypothermia.

The objective was to apply a population model to describe the time course and variability of serum creatinine (sCr) in (near)term neonates with moderate to severe encephalopathy during and after therapeutic hypothermia (TH). The data consisted of sCr observations up to 10 days of postnatal age in neonates who underwent TH during the first 3 days after birth. Available covariates were birth weight (BWT), gestational age (GA), survival, and acute kidney injury (AKI). A previously published population model of sCr kinetics in neonates served as the base model. This model predicted not only sCr but also the glomerular filtration rate normalized by its value at birth (GFR/GFR0). The model was used to compare the TH neonates with a reference full term non-asphyxiated population of neonates. The estimates of the model parameters had good precision and showed high between subject variability. AKI influenced most of the estimated parameters denoting a strong impact on sCr kinetics and GFR. BWT and GA were not significant covariates. TH transiently increased [Formula: see text] in TH neonates over the first days compared to the reference group. Asphyxia impacted not only GFR, but also the [Formula: see text] synthesis rate. We also observed that AKI neonates exhibit a delayed onset of postnatal GFR increase and have a higher [Formula: see text] synthesis rate compared to no-AKI patients. Our findings show that the use of [Formula: see text] as marker of renal function in asphyxiated neonates treated with TH to guide dose selection for renally cleared drugs is challenging, while we captured the postnatal sCr patterns in this specific population.

Left Ventricular Function and Dimensions Are Altered Early in Infants Developing Brain Injury in the Setting of Neonatal Encephalopathy.

We evaluated the association between left cardiac 3-dimensional echocardiographic parameters and brain injury in a single-center prospective study of neonates with neonatal encephalopathy. On day 2 of life, neonates with brain injury had greater left ventricle end-diastolic and stroke volume but also greater peak global circumferential strain detected by 3-dimensional echocardiogram.

A comparison of altered white matter microstructure in youth born with congenital heart disease or born preterm.

Introduction: Alterations to white matter microstructure as detected by diffusion tensor imaging have been documented in both individuals born with congenital heart disease (CHD) and individuals born preterm. However, it remains unclear if these disturbances are the consequence of similar underlying microstructural disruptions. This study used multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) and neurite orientation dispersion and density imaging (NODDI) to characterize and compare alterations to three specific microstructural elements of white matter - myelination, axon density, and axon orientation - in youth born with CHD or born preterm. Methods: Participants aged 16 to 26 years with operated CHD or born ≤33 weeks gestational age and a group of healthy peers of the same age underwent a brain MRI including mcDESPOT and high angular resolution diffusion imaging acquisitions. Using tractometry, average values of myelin water fraction (MWF), neurite density index (NDI), and orientation dispersion index (ODI) were first calculated and compared between groups for 30 white matter bundles. Afterwards, bundle profiling was performed to further characterize the topology of the detected microstructural alterations. Results: The CHD and preterm groups both presented with widespread bundles and bundle segments with lower MWF, accompanied by some occurrences of lower NDI, relative to controls. While there were no differences in ODI between the CHD and control groups, the preterm group presented with both higher and lower ODI compared to the control group and lower ODI compared to the CHD group. Discussion: While youth born with CHD or born preterm both presented with apparent deficits in white matter myelination and axon density, youth born preterm presented with a unique profile of altered axonal organization. Future longitudinal studies should aim to better understand the emergence of these common and distinct microstructural alterations, which could orient the development of novel therapeutic approaches.

Long-term consequences of neonatal encephalopathy in the hypothermia era: protocol for a follow-up cohort study at 9 years of age.

INTRODUCTION: Therapeutic hypothermia (TH) became the standard of care treatment for neonates with moderate and severe neonatal encephalopathy (NE) in most industrialized countries about 10 years ago. Although TH is effective in reducing mortality and the incidence of severe developmental disabilities, the recent literature converges in reporting frequent cognitive and behavioural difficulties at school entry in children with NE-TH. Although these challenges are deemed minor compared with cerebral palsy and intellectual disability, their impacts on a child's self-determination and family's well-being are quite significant. Therefore, the nature and extent of these difficulties need to be comprehensively described so that appropriate care can be offered. METHODS AND ANALYSIS: The current study will be the largest follow-up study of neonates with NE treated with TH to characterize their developmental outcomes and associated brain structural profiles at 9 years of age. Specifically, we will compare executive function, attention, social cognition, behaviour, anxiety, self-esteem, peer problems, brain volume, cortical features, white matter microstructure and myelination between children with NE-TH and matched peers without NE. Associations of perinatal risk factors and structural brain integrity with cognitive, behavioural and psycho-emotional deficits will be evaluated to inform about the potential aggravating and protective factors associated with function. ETHICS AND DISSEMINATION: This study is supported by the Canadian Institute of Health Research (202203PJT-480065-CHI-CFAC-168509), and received approval from the Pediatric Ethical Review Board of the McGill University Health Center (MP-37-2023-9320). The study findings will be disseminated in scientific journals and conferences and presented to parental associations and healthcare providers to inform best practices. TRIAL REGISTRATION NUMBER: NCT05756296.

Characteristics of Children With Cerebral Palsy in the Post-Therapeutic Hypothermia Era.

Objectives: To explore the profile of children with cerebral palsy secondary to intrapartum asphyxia treated with therapeutic hypothermia after birth and to compare characteristics of children treated with therapeutic hypothermia with mild vs severe cerebral palsy outcome. Study Design: We identified all children treated with therapeutic hypothermia for intrapartum asphyxia in a single-center tertiary-level neonatal intensive care unit from 2008 to 2018 with a cerebral palsy outcome. We collected perinatal and outcome measures from patient charts. We searched the literature for characteristics of children with cerebral palsy prior to therapeutic hypothermia (historical cohort) to compare to our cohort. We subdivided our cohort into mild vs severe cerebral palsy and compared neonatal characteristics to identify predictors of severe phenotype. Results: Thirty of 355 cooled neonates (8%) developed cerebral palsy. More children had spastic quadriparesis and epilepsy, and fewer had visual impairment in the post-therapeutic hypothermia era compared to the historical cohort, but had similar Gross Motor Function Classification System scores. In our cohort, more children had severe (19 of 30, 63%) compared to mild cerebral palsy (11 of 30, 37%). The severe group had higher mean birth weight, lower 5- and 10-minute Apgar scores, and more often white matter injury with associated deep gray matter injury or near-total injury pattern (P < .05). Conclusions: Our data demonstrated more infants with severe rather than mild cerebral palsy in our cohort treated with therapeutic hypothermia. Birthweight, 5- and 10-minute Apgar scores, and magnetic resonance imaging (MRI) findings were significantly different between mild and severe phenotype groups. Our findings can guide clinicians how to better weigh these factors, when counseling parents in the neonatal period.

Exposure to Maternal Diabetes during Pregnancy Is Associated with Aggravated Short-Term Neonatal and Neurological Outcomes following Perinatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: Infants of diabetic mothers (IDM) are at higher risk of perinatal morbidities and glycemic instability, but the impact of maternal diabetes on neonatal and neurological short-term outcomes of neonates with hypoxic-ischemic encephalopathy (HIE) remains poorly described. Our objective was to determine the impact of maternal diabetes on neonatal and neurological short-term outcomes following neonatal HIE. STUDY DESIGN: This was a retrospective single-center study including 102 term neonates with HIE who received therapeutic hypothermia (TH) treatment between 2013 and 2020. Multiple regression analysis was used to assess the relationship between the presence of maternal diabetes and short-term outcomes. RESULTS: Neonates with HIE and maternal diabetes exposure had a significantly lower gestational age at birth (38.6 vs. 39.7 weeks of gestation, p = 0.005) and a significantly higher mean birth weight (3,588 ± 752 vs. 3,214 ± 514 g, p = 0.012). IDM with HIE were ventilated for longer duration (8 vs. 4 days, p = 0.0047) and had a longer neonatal intensive care unit (NICU) stay (18 vs. 11 days, p = 0.0483) as well as took longer time to reach full oral feed (15 vs. 7 days, p = 0.0432) compared with neonates of nondiabetic mother. Maternal diabetes was also associated with an increased risk of death or abnormal neurological examination at discharge in neonates with HIE (odds ratio: 6.41 [1.54-26.32]). CONCLUSION: In neonates with HIE, maternal diabetes is associated with an increased risk of death or short-term neonatal morbidities, such as longer duration of ventilation, prolonged neonatal stay, greater need for tube feeding, and being discharged with an abnormal neurological examination. Strategies to prevent, reduce, or better control maternal diabetes during pregnancy should be prioritized to minimize complications after perinatal asphyxia. KEY POINTS: · Maternal DB is associated with unfavorable outcomes.. · IDM have longer ventilatory support and tube feeding.. · IDM have higher risk of abnormal neurological examination..

Variations in care of neonates during therapeutic hypothermia: call for care practice bundle implementation.

BACKGROUND: Therapeutic hypothermia (TH) is the gold-standard treatment for moderate and severe neonatal encephalopathy (NE). Care during TH has implications for long-term outcomes. Outcome variability exists among neonatal intensive care units (NICUs) in Canada, but care variations are not understood well. This study examines variations in care practices for neonates with NE treated with TH in NICUs across Canada. METHODS: A non-anonymous, web-based questionnaire was emailed to tertiary NICUs in Canada providing TH for NE to assess care practices during the first days of life and neurodevelopmental follow-up. RESULTS: Ninety-two percent (24/26) responded. Centres followed national guidelines regarding the use of the modified Sarnat score to assess the initial severity of NE, the need to initiate TH within the first 6 h of birth, and the importance of follow-up. However, other practices varied, including ventilation mode, definition/treatment of hypotension, routine echocardiography, use of sedation, use of electroencephalogram (EEG), MRI timing, placental analysis, and follow-up duration. CONCLUSIONS: NICUs across Canada follow available national guidelines, but variations exist in practices for managing NE during TH. Development and implementation of a consensus-based care bundle for neonates during TH may reduce practice variability and improve outcomes. IMPACT: This survey describes the current HIE care practices and variation among tertiary centres in Canada. Variations exist in the care of neonates with NE treated with TH in NICUs across Canada. This paper Identifies areas of variation that are not discussed in detail in the national guidelines and will help to set up quality improvement initiatives. Elucidating the variation in care practices calls for the creation and implementation of a national, consensus-based care bundle, with the objective to improve the outcomes of these critically ill neonates.

Optimizing timing and frequency of head ultrasound screening for severe brain injury among preterm infants born <32 weeks' gestation.

OBJECTIVE: To develop a head ultrasound (HUS) screening protocol for infants born <32 weeks gestational age (GA) that accurately identifies severe brain injury (SBI) while minimizing resource use. STUDY DESIGN: Retrospective cohort study of infants born <32 weeks GA, admitted to a level 3 neonatal intensive care unit between 2011 and 2017. Timing and results of each HUS were reviewed. SBI was defined as intraventricular hemorrhage grade ≥3 and/or periventricular leukomalacia. Logistic regression models were used to identify risk factors and evaluate the predictive value of HUS at different time points during hospitalization. RESULTS: Of 651 included infants, 71 (11%) developed SBI. Risk factors for SBI were GA at birth <29 weeks (adjusted odds ratio (aOR) 2.87, 95% confidence interval (CI) 1.50-5.48), vasopressors on admission (aOR 3.08, 95%CI 1.38-6.88) and mechanical ventilation on admission (aOR 2.50, 95%CI 1.33-4.68). Infants were classified into three risk groups based on these risk factors, and combinations of 1-5 HUS time points were evaluated to determine the optimal number and timing of HUS for each group. The optimal number of screening HUS ranged from 1 for low-risk to 2 for high-risk infants. Adopting a screening protocol using the number and timing of HUS optimized by risk group could reduce the total number of HUS performed by 40% and the median number of HUS per infant from 3 (IQR 2-4) to 2 (IQR 1-3) (p < .01). CONCLUSIONS: Implementation of a risk factor-based HUS screening protocol can help reduce resource use while maintaining high sensitivity for detecting SBI.

Discussing brain magnetic resonance imaging results for neonates with hypoxic-ischemic encephalopathy treated with hypothermia: A challenge for clinicians and parents.

Context: Clinicians use brain magnetic resonance imaging (MRI) to discuss neurodevelopmental prognosis with parents of neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH). Purpose: To investigate how clinicians and parents discuss these MRI results in the context of HIE and TH and how these discussions could be facilitated and more meaningful for parents. Procedures: Mixed-methods surveys with open-ended and closed-ended questions were completed by two independent groups. (1) Clinicians responded to clinical vignettes of neonates with HIE treated with TH with various types of clinical features, evolution and extent of brain injury and questions about how they discuss brain MRI results in this context. (2) Parents of children with HIE treated with TH responded to questions about the discussion of MRI that they had while still in the neonatal intensive care unit and were asked to place it in perspective with the outcomes of their child when he/she reached at least 2 years of age. Open-ended responses were analyzed using a thematic analysis approach. Closed-ended responses are presented descriptively. Results: Clinicians reported uncertainty, lack of confidence, and limitations when discussing brain MRI results in the context of HIE and TH. Brain MRI results were "usually" (53%) used in the prognostication discussion. When dealing with day-2 brain MRIs performed during TH, most clinicians (40%) assumed that the results of these early MRIs were only "sometimes" accurate and only used them "sometimes" (33%) to discuss prognosis; a majority of them (66%) would "always" repeat imaging at a later time-point to discuss prognosis. Parents also struggled with this uncertainty, but did not discuss limitations of MRI as often. Parents raised the importance of the setting where the discussion took place and the importance to inform them as quickly as possible. Clinicians identified strategies to improve these discussions, including interdisciplinary approach, formal training, and standardized approach to report brain MRI. Parents highlighted the importance of communication skills, the stress, the hope surrounding their situation, and the need to receive answers as soon as possible. The importance of showing the pictures or making representative drawing of the injury, but also highlighting the not-injured brain, was also highlighted by parents. Conclusions: Discussing brain MRI results for neonates with HIE treated with TH are challenging tasks for clinicians and daunting moments for parents.

Outcomes of Neonates with a 10-min Apgar Score of Zero: A Systematic Review and Meta-Analysis.

INTRODUCTION: The Apgar score is a standardized method of assessing the primary adaptation and clinical status of a neonate after birth. Our objective was to systematically review and meta-analyze the survival and the survival without moderate-to-severe neurodevelopmental impairment (NDI) of neonates with a 10-min Apgar score of zero. METHODS: Six electronic databases were searched for reports published until November 2021 of neonates with a 10-min Apgar score of zero. Risk of bias was assessed using the Newcastle-Ottawa scale for cohort studies and the Joanna Briggs Institute Critical Appraisal Checklist for case series/reports. Meta-analyses of the proportion of outcomes were conducted using a random-effects model for studies published after year 2000 and reporting >5 neonates. Meta-regression using the median year of the study period and subgroup analyses by treatment with therapeutic hypothermia and by gestational age were conducted. RESULTS: Twenty-eight studies of 820 neonates with moderate risk of bias were included. Survival was 40% (95% confidence interval 30-50%, 16 studies, 646 neonates, I2 = 83%), and it increased by 2.3% per year (95% CI 1.3-3.2%, p < 0.001). Survival without moderate-to-severe NDI was 19% (95% confidence interval 11-27%, 13 studies, 211 neonates, I2 = 62%). Survival was higher for neonates who received therapeutic hypothermia and for those with a gestational age ≥32 weeks compared to <32 weeks. CONCLUSION: Approximately 2 in 5 neonates with a 10-min Apgar score of zero survived, and 1 in 5 survive without moderate-to-severe NDI survived. Survival has improved over the years, especially since the era of therapeutic hypothermia.

Serum Creatinine Patterns in Neonates Treated with Therapeutic Hypothermia for Neonatal Encephalopathy.

INTRODUCTION: There is large variability in kidney function and injury in neonates with neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH). Acute kidney injury (AKI) definitions that apply categorical approaches may lose valuable information about kidney function in individual patients. Centile serum creatinine (SCr) over postnatal age (PNA) may provide more valuable information in TH neonates. METHODS: Data from seven TH neonates and one non-TH-treated, non-NE control cohorts were pooled in a retrospective study. SCr centiles over PNA, and AKI incidence (definition: SCr ↑≥0.3 mg/dL within 48 h, or ↑ ≥1.5 fold vs. the lowest prior SCr within 7 days) and mortality were calculated. Repeated measurement linear models were applied to SCr trends, modeling SCr on PNA, birth weight or gestational age (GA), using heterogeneous autoregressive residual covariance structure and maximum likelihood methods. Findings were compared to patterns in the control cohort. RESULTS: Among 1,136 TH neonates, representing 4,724 SCr observations, SCr (10th-25th-50th-75th-90th-95th) PNA centiles (day 1-10) were generated. In TH neonates, the AKI incidence was 132/1,136 (11.6%), mortality 193/1,136 (17%). AKI neonates had a higher mortality (37.2-14.3%, p < 0.001). Median SCr patterns over PNA were significantly higher in nonsurvivors (p < 0.01) or AKI neonates (p < 0.001). In TH-treated neonates, PNA and GA or birth weight explained SCr variability. Patterns over PNA were significantly higher in TH neonates to controls (801 neonates, 2,779 SCr). CONCLUSIONS: SCr patterns in TH-treated NE neonates are specific. Knowing PNA-related patterns enable clinicians to better assess kidney function and tailor pharmacotherapy, fluids, or kidney supportive therapies.

Outcomes of infants with hypoxic-ischemic encephalopathy during COVID-19 pandemic lockdown in Canada: a cohort study.

PURPOSE: To evaluate change in the severity of hypoxic-ischemic encephalopathy (HIE) and associated morbidities between pre- and during COVID-19 pandemic periods in Canada. METHODS: We conducted a retrospective cohort study extracting the data from level-3 NICUs participating in Canadian Neonatal Network (CNN). The primary outcome was a composite of death in the first week after birth and/or stage 3 HIE (Sarnat and Sarnat). Secondary outcomes included rate and severity of HIE among admitted neonates, overall mortality, brain injury on magnetic resonance imaging (MRI), neonates requiring resuscitation, organ dysfunction, and therapeutic hypothermia (TH) usage. We included 1591 neonates with gestational age ≥ 36 weeks with HIE during the specified periods: pandemic cohort from April 1st to December 31st of 2020; pre-pandemic cohort between April 1st and December 31st of 2017, 2018, and 2019. We calculated the odds ratio (OR) and confidence intervals (CI). RESULTS: We observed no significant difference in the primary outcome (15% vs. 16%; OR 1.08; 95%CI 0.78-1.48), mortality in the first week after birth (6% vs. 6%; OR 1.10, 95%CI 0.69-1.75), neonates requiring resuscitation, organ dysfunction, TH usage, or rate of brain injury. In the ad hoc analysis, per 1000 live births, there was an increase in the rate of infants with HIE and TH use. CONCLUSIONS: Severity of HIE, associated morbidities, and mortality were not significantly different during the pandemic lockdown compared to a pre-pandemic period in Canada. Anticipated risks and difficulties in accessing healthcare have not increased the mortality and morbidities in neonates with HIE in Canada.

The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates.

Sildenafil is a recognized treatment for patients suffering from erectile dysfunction and pulmonary hypertension. However, new evidence suggests that it may have a neuroprotective and a neurorestorative role in the central nervous system of both adults and neonates. Phosphodiesterase type 5-the target of sildenafil-is distributed in many cells throughout the body, including neurons and glial cells. This study is a comprehensive review of the demonstrated effects of sildenafil on the brain with respect to its function, extent of injury, neurons, neuroinflammation, myelination, and cerebral vessels.

Variations in practices and outcomes of neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia across tertiary NICUs in Canada.

OBJECTIVE: To characterize variations in practices and outcomes for neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH) across Canadian tertiary Neonatal Intensive Care Units (NICUs). STUDY DESIGN: Retrospective study of neonates admitted for HIE and treated with TH in 24 tertiary NICUs from the Canadian Neonatal Network, 2010-2020. The two primary outcomes of mortality before discharge and MRI-detected brain injury were compared across NICUs using adjusted standardized ratios (SR) with 95% CI. RESULTS: Of the 3261 neonates that received TH, 367 (11%) died and 1033 (37%) of the 2822 with MRI results had brain injury. Overall, rates varied significantly across NICUs for mortality (range 5-17%) and brain injury (range 28-51%). Significant variations in use of inotropes, inhaled nitric oxide, blood products, and feeding during TH were identified (p values < 0.01). CONCLUSION: Significant variations exist in practices and outcomes of HIE neonates treated with hypothermia across Canada.

Protocol for the Birth Asphyxia in African Newborns (Baby BRAiN) Study: a Neonatal Encephalopathy Feasibility Cohort Study.

BACKGROUND: Neonatal encephalopathy (NE) is a leading cause of child mortality worldwide and contributes substantially to stillbirths and long-term disability. Ninety-nine percent of deaths from NE occur in low-and-middle-income countries (LMICs). Whilst therapeutic hypothermia significantly improves outcomes in high-income countries, its safety and effectiveness in diverse LMIC contexts remains debated. Important differences in the aetiology, nature and timing of neonatal brain injury likely influence the effectiveness of postnatal interventions, including therapeutic hypothermia. METHODS: This is a prospective pilot feasibility cohort study of neonates with NE conducted at Kawempe National Referral Hospital, Kampala, Uganda. Neurological investigations include continuous video electroencephalography (EEG) (days 1-4), serial cranial ultrasound imaging, and neonatal brain Magnetic Resonance Imaging and Spectroscopy (MRI/ MRS) (day 10-14). Neurodevelopmental follow-up will be continued to 18-24 months of age including Prechtl's Assessment of General Movements, Bayley Scales of Infant Development, and a formal scored neurological examination. The primary outcome will be death and moderate-severe neurodevelopmental impairment at 18-24 months. Findings will be used to inform explorative science and larger trials, aiming to develop urgently needed neuroprotective and neurorestorative interventions for NE applicable for use in diverse settings. DISCUSSION: The primary aims of the study are to assess the feasibility of establishing a facility-based cohort of children with NE in Uganda, to enhance our understanding of NE in a low-resource sub-Saharan African setting and provide infrastructure to conduct high-quality research on neuroprotective/ neurorestorative strategies to reduce death and disability from NE. Specific objectives are to establish a NE cohort, in order to 1) investigate the clinical course, aetiology, nature and timing of perinatal brain injury; 2) describe electrographic activity and quantify seizure burden and the relationship with adverse outcomes, and; 3) develop capacity for neonatal brain MRI/S and examine associations with early neurodevelopmental outcomes.