Characteristics and outcomes of neonates with intrapartum asphyxia managed with therapeutic hypothermia in a public tertiary hospital in South Africa.

BACKGROUND: In randomized clinical trials, therapeutic hypothermia (TH) has been shown to reduce death and/or moderate-to-severe disability in neonates with hypoxic ischemic encephalopathy (HIE) in high-income countries, while this has not consistently been the case in low-and middle-income countries (LMICs). Many studies reporting on outcomes of neonates with HIE managed with TH are those conducted under controlled study conditions, and few reporting in settings where this intervention is offered as part of standard of care, especially from LMICs. In this study we report on short-term outcomes of neonates with moderate-to-severe HIE where TH was offered as part of standard of care. OBJECTIVE: To determine characteristics and mortality rate at hospital discharge in neonates with moderate-to-severe HIE. METHODS: Hospital records of neonates with intrapartum asphyxia were reviewed for clinical findings, management with TH (cooled or non-cooled) and mortality at hospital discharge. Inclusion criteria were birthweight ≥ 1800 g, gestational age ≥ 36 weeks and moderate-to-severe HIE. Comparisons were made between survivors and non-survivors in cooled and/or non-cooled neonates. RESULTS: Intrapartum asphyxia was diagnosed in 856 neonates, with three having no recorded HIE status; 30% (258/853) had mild HIE, and 595/853 (69%) with moderate-to-severe HIE. The overall incidence of intrapartum asphyxia was 8.8/1000 live births. Of the 595 with moderate-to-severe HIE, three had no records on cooling and 67% (399/592) were cooled. Amongst 193 non-cooled neonates, 126 (67%) had documented reasons for not being cooled with common reasons being a moribund neonate (54.0%), equipment unavailability (11.1%), pulmonary hypertension (9.5%), postnatal age > 6 h on admission (8.7%), and improvement in severity of encephalopathy (8.7%). Overall mortality was 29.0%, being 17.0% and 53.4% in cooled and non-cooled infants respectively. On multivariate analysis, the only factor associated with mortality was severe encephalopathy. CONCLUSION: Overall mortality in neonates with moderate-to-severe HIE was 29.0% and 17.0% in those who were cooled. Cooling was not offered to all neonates mainly because of severe clinical illness, equipment unavailability and delayed presentation, making it difficult to assess overall impact of this intervention. Prospective clinical studies need to be conducted in LMIC to further assess effect of TH in short and long-term outcomes.

Outcome and prognostication after cardiac arrest.

The outcome after out-of-hospital cardiac arrest has historically been grim at best. The current overall survival rate of patients admitted to a hospital is approximately 10%, making cardiac arrest one of the leading causes of death in the United States. The situation is improving with the incorporation of therapeutic temperature modulation, aggressive prevention of secondary brain injury, and improved access to advanced cardiovascular support, all of which have decreased mortality and allowed for better outcomes. Mortality after cardiac arrest is often the direct result of active withdrawal of life-sustaining therapy based on the perception that neurological recovery is not possible. This reality highlights the importance of providing accurate estimates of neurological prognosis to decision makers when discussing goals of care. The current standard of care for assessing neurological status in patients with hypoxic-ischemic encephalopathy emphasizes a multimodal approach that includes five elements: (1) neurological examination off sedation, (2) continuous electroencephalography, (3) serum neuron-specific enolase levels, (4) magnetic resonance brain imaging, and (5) somatosensory-evoked potential testing. Sophisticated decision support systems that can integrate these clinical, imaging, and biomarker and neurophysiologic data and translate it into meaningful projections of neurological outcome are urgently needed.

Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: a nationwide propensity score-matched analysis.

OBJECTIVE: Therapeutic hypothermia (TH) for neonatal hypoxic-ischaemic encephalopathy (HIE), delivered mainly in tertiary cooling centres (CCs), reduces mortality and neurodisability. It is unknown if birth in a non-cooling centre (non-CC), without active TH, impacts short-term outcomes. DESIGN: Retrospective cohort study using National Neonatal Research Database and propensity score-matching. SETTING: UK neonatal units. PATIENTS: Infants ≥36 weeks gestational age with moderate or severe HIE admitted 2011-2016. INTERVENTIONS: Birth in non-CC compared with CC. MAIN OUTCOME MEASURES: Primary outcome was survival to discharge without recorded seizures. Secondary outcomes were recorded seizures, mortality and temperature on arrival at CCs following transfer. RESULTS: 5059 infants were included with 2364 (46.7%) born in non-CCs. Birth in a CC was associated with improved survival without seizures (35.1% vs 31.8%; OR 1.15, 95% CI 1.02 to 1.31; p=0.02), fewer seizures (60.7% vs 64.6%; OR 0.84, 95% CI 0.75 to 0.95, p=0.007) and similar mortality (15.8% vs 14.4%; OR 1.11, 95% CI 0.93 to 1.31, p=0.20) compared with birth in a non-CC. Matched infants from level 2 centres only had similar results, and birth in CCs was associated with greater seizure-free survival compared with non-CCs. Following transfer from a non-CC to a CC (n=2027), 1362 (67.1%) infants arrived with a recorded optimal therapeutic temperature but only 259 (12.7%) of these arrived within 6 hours of birth. CONCLUSIONS: Almost half of UK infants with HIE were born in a non-CC, which was associated with suboptimal hypothermic treatment and reduced seizure-free survival. Provision of active TH in non-CC hospitals prior to upward transfer warrants consideration.

Efficacy of erythropoietin alone in treatment of neonates with hypoxic-ischemic encephalopathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Multiple clinical trials have demonstrated the safety and efficacy of erythropoietin in improving neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE). It is undoubtedly urgent to include only randomized controlled trials (RCTs) for more standardized systematic reviews and meta-analyses. The purpose of this study is to examine whether erythropoietin reduces the risk of death and improve neurodevelopmental disorders in infants with HIE. METHODS: The electronic databases of Cochrane Library, EMBASE, PubMed, and Web of Science were searched from the inception to June 2021 using the following key terms: "erythropoietin," "hypoxic-ischemic encephalopathy," and "prospective," for all relevant RCTs. Only English publications were included. The primary outcome was mortality rate. Secondary outcomes included neurodevelopmental disorders, brain injury, and cognitive impairment. The Cochrane risk of bias tool was independently used to evaluate the risk of bias of included RCTs by 2 reviewers. RESULTS: We hypothesized that group with erythropoietin would provide better therapeutic benefits compared with control group. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/FERUS.

Immunohistochemistry in postmortem diagnosis of acute cerebral hypoxia and ischemia: A systematic review.

BACKGROUND: : Discovery of evidence of acute brain ischemia or hypoxia and its differentiation from agonal hypoxia represents a task of interest but extremely difficult in forensic neuropathology. Generally, more than 50% of forensic autopsies indicate evidence of brain induced functional arrest of the organ system, which can be the result of a hypoxic/ischemic brain event. Even if the brain is the target organ of hypoxic/ischemic damage, at present, there are no specific neuropathological (macroscopic and histological) findings of hypoxic damage (such as in drowning, hanging, intoxication with carbon monoxide) or acute ischemia. In fact, the first histological signs appear after at least 4 to 6 hours. Numerous authors have pointed out how an immunohistochemical analysis could help diagnose acute cerebral hypoxia/ischemia.Data sources: This review was based on articles published in PubMed and Scopus databases in the past 25 years, with the following keywords "immunohistochemical markers," "acute cerebral ischemia," "ischemic or hypoxic brain damage," and "acute cerebral hypoxia". OBJECTIVES: : Original articles and reviews on this topic were selected. The purpose of this review is to analyze and summarize the markers studied so far and to consider the limits of immunohistochemistry that exist to date in this specific field of forensic pathology. RESULTS: : We identified 13 markers that had been examined (in previous studies) for this purpose. In our opinion, it is difficult to identify reliable and confirmed biomarkers from multiple studies in order to support a postmortem diagnosis of acute cerebral hypoxia/ischemia. Microtubule-associated protein 2 (MAP2) is the most researched marker in the literature and the results obtained have proven to be quite useful. CONCLUSION: Immunohistochemistry has provided interesting and promising results, but further studies are needed in order to confirm and apply them in standard forensic practice.

Trends and predictors of in-hospital mortality among babies with hypoxic ischaemic encephalopathy at a tertiary hospital in Nigeria: A retrospective cohort study.

BACKGROUND: Globally, approximately 9 million neonates develop perinatal asphyxia annually of which about 1.2 million die. Majority of the morbidity and mortality occur in Low and middle-income countries. However, little is known about the current trend in incidence, and the factors affecting mortality from hypoxic ischaemic encephalopathy (HIE), in Nigeria. OBJECTIVE: We assessed the trends in incidence and fatality rates and evaluated the predictors of mortality among babies admitted with HIE over five years at the Lagos University Teaching Hospital. METHODS: A temporal trend analysis and retrospective cohort study of HIE affected babies admitted to the neonatal unit of a Nigerian Teaching Hospital was conducted. The socio-demographic and clinical characteristics of the babies and their mothers were extracted from the neonatal unit records. Kaplan-Meir plots and Multivariable Cox proportional hazard ratio was used to evaluate the survival experienced using Stata version 16 (StataCorp USA) statistical software. RESULTS: The median age of the newborns at admission was 26.5 (10-53.5) hours and the male to female ratio was 2.1:1. About one-fifth (20.8%) and nearly half (47.8%) were admitted within 6 hours and 24 hours of life respectively, while majority (84%) of the infants were out-born. The prevalence and fatality rate of HIE in our study was 7.1% and 25.3% respectively. The annual incidence of HIE among the hospital admissions declined by 1.4% per annum while the annual fatality rate increased by 10.3% per annum from 2015 to 2019. About 15.7% died within 24 hours of admission. The hazard of death was related to the severity of HIE (p = 0.001), antenatal booking status of the mother (p = 0.01) and place of delivery (p = 0.03). CONCLUSION: The case fatality rate of HIE is high and increasing at our centre and mainly driven by the pattern of admission of HIE cases among outborn babies. Thus, community level interventions including skilled birth attendants at delivery, newborn resuscitation trainings for healthcare personnel and capacity building for specialized care should be intensified to reduce the burden of HIE.

Trends in the incidence and management of hypoxic-ischaemic encephalopathy in the therapeutic hypothermia era: a national population study.

OBJECTIVE: Hypoxic-ischaemic encephalopathy (HIE) remains a leading cause of neonatal mortality and neurodisability. We aimed to determine the incidence of HIE and management patterns against national guidelines. DESIGN: Retrospective cohort study using the National Neonatal Research Database. SETTING: Neonatal units in England and Wales. PATIENTS: Infants 34-42 weeks gestational age (GA) with a recorded diagnosis of HIE. MAIN OUTCOMES: Incidence of HIE, mortality and treatment with therapeutic hypothermia (TH) were the main outcomes. Temporal changes were compared across two epochs (2011-2013 and 2014-2016). RESULTS: Among 407 462 infants admitted for neonatal care, 12 195 were diagnosed with HIE. 8166 infants ≥36 weeks GA had moderate/severe HIE, 62.1% (n=5069) underwent TH and mortality was 9.3% (n=762). Of infants with mild HIE (n=3394), 30.3% (n=1027) underwent TH and 6 died. In late preterm infants (34-35 weeks GA) with HIE (n=635, 5.2%), 33.1% (n=210) received TH and 13.1% (n=83) died. Between epochs (2011-2013 vs 2014-2016), mortality decreased for infants ≥36 weeks GA with moderate/severe HIE (17.5% vs 12.3%; OR 0.69, 95% CI 0.59 to 0.81, p<0.001). Treatment with TH increased significantly between epochs in infants with mild HIE (24.9% vs 35.8%, p<0.001) and those born late preterm (34.3% vs 46.6%, p=0.002). CONCLUSIONS: Mortality of infants ≥36 weeks GA with moderate/severe HIE has reduced over time, although many infants diagnosed with moderate/severe HIE do not undergo TH. Increasingly, mild HIE and late preterm infants with HIE are undergoing TH, where the evidence base is lacking, highlighting the need for prospective studies to evaluate safety and efficacy in these populations.

Hypoxic Ischemic Encephalopathy in Units Reporting to the Ibero-American Society of Neonatology Network: Prevalence and Mortality.

INTRODUCTION: Hypoxic ischemic encephalopathy is a neurological condition occurring immediately after birth following a perinatal asphytic episode. Therapeutic hypothermia is a safe and effective intervention to reduce mortality and major disability in survivors. In Latin America, perinatal asphyxia is a major problem, but no data are available characterizing its current situation in the region or the impact of hypoxic ischemic encephalopathy on its management. OBJECTIVE: Understand the prevalence, mortality and use of therapeutic hypothermia in newborns at ≥36 weeks gestational age with hypoxic ischemic encephalopathy admitted to neonatal units reporting to the Ibero-American Society of Neonatology Network. METHODS: The Ibero-American Society of Neonatology Network groups various neonatology centers in Latin America that share information and collaborate on research and medical care. We evaluated data on newborns with ≥36 weeks gestational age reported during 2019. Each unit received a guide with definitions and questions based on the Society's 7th Clinical Consensus. Evaluated were encephalopathy frequency and severity, Apgar score, need for resuscitation at birth, use of therapeutic hypothermia and clinical evolution at discharge. Our analysis includes descriptive statistics and comparisons made using the chi-square test. RESULTS: We examined reports of 2876 newborns from 33 units and 6 countries. In 2849 newborns with available data, hypoxic encephalopathy prevalence was 5.1% (146 newborns): 27 (19%) mild, 36 (25%) moderate, 43 (29%) severe, and 40 (27%) of unknown intensity. In those with moderate and severe encephalopathy, frequencies of Apgar scores ≤3 at the first minute (p = 0.001), Apgar scores ≤3 at the fifth minute (p ⟨0.001) and advanced resuscitation (p = 0.007) were higher. Therapeutic hypothermia was performed in only 13% of newborns (19). Neonatal mortality from encephalopathy was 42% (61). CONCLUSIONS: Hypoxic ischemic encephalopathy is a neonatal condition that results in high mortality and severe neurological sequelae. In this study, the overall prevalence was 5.1% with a mortality rate of 42%. Although encephalopathy was moderate or severe in 54% of reported cases, treatment with hypothermia was not performed in 87% of newborns. These data reflect a regional situation that requires urgent action.

Factors associated with neonatal mortality in a tertiary hospital in Phnom Penh, Cambodia.

This study aimed to identify hospital neonatal mortality rate (NMR) and the causes of neonatal deaths, and to understand risk factors associated with neonatal mortality in a national tertiary hospital in Cambodia. The study included all newborn infants, aged 0-28 days old, hospitalized in the Pediatrics department of Khmer-Soviet Friendship Hospital between January 2016 and December 2017. In total, 925 infants were included in the study. The mean gestational age was 35.9 weeks (range, 24-42 weeks). Preterm infants and low birth weight accounted for 47.5% and 56.7%, respectively. With respect to payment methods, the government (53.5%) and non-governmental organizations (NGO) (13.7%) paid the fees as the families were not in a financial position to do so. The hospital NMR at the Pediatrics department was 9.3%. Respiratory distress syndrome (37.2%) was the main cause of deaths followed by hypoxic-ischemic encephalopathy (31.4%) and neonatal infection (21.0%). Factors associated with neonatal mortality were Apgar score at 5th minute <7 (adjusted odds ratio (AOR) = 3.57), payment by the government or NGO (AOR = 11.32), admission due to respiratory distress (AOR = 11.94), and hypothermia on admission (AOR = 9.41). The hospital NMR in the Pediatrics department was 9.3% (95% confidence interval 7.50-11.35) at Khmer-Soviet Friendship Hospital; prematurity and respiratory distress syndrome were the major causes of neonatal mortality. Introducing continuous positive airway pressure machine for respiratory distress syndrome and creating neonatal resuscitation guidelines and preventing hypothermia in delivery rooms are required to reduce the high NMR.

Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin.

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine Macaca nemestrina were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h-6h, and significantly lower MCP-4 and MDC at 24 h-72h, respectively. IL-12p40 was lower at 24 h-72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.

Intrapartum fetal monitoring and perinatal risk factors of neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) in term infants, is a major cause of neonatal mortality and severe neurologic disability. OBJECTIVES: To identify in labor fetal monitoring characteristic patterns and perinatal factors associated with neonatal HIE. STUDY DESIGN: Single-center retrospective case-control study between 2010 and 2017. Cases clinically diagnosed with neonatal HIE treated by therapeutic hypothermia according to strict criteria (HIE-TH) were compared to a group of neonates born in the same period, gestational age-matched diagnosed with fetal distress according to fetal monitoring interpretation that was followed by prompt delivery, without subsequent HIE or therapeutic hypothermia (No-HIE). The primary outcome of the study was the electronic fetal monitoring (EFM) pattern during 60 min prior to delivery; the secondary outcome was the identification of perinatal associated factors. RESULTS: 54 neonates with HIE were treated by therapeutic hypothermia. EFM parameters most predictive of HIE-TH were indeterminate baseline heart rate OR = 47.297, 95% (8.17-273.76) p < 0.001, bradycardia OR = 15.997 95% (4.18-61.18) p < 0.001, low variability OR = 10.224, 95% (2.71-38.45) p < 0.001, higher baseline of the fetal heart rate calculated for each increment of 1 BPM OR = 1.0547, 95% (1.001-1.116) p = 0.047. Rupture of a previous uterine cesarean scar and placental abruption were characteristic of the HIE-TH group 14.8% vs. 1% p < 0.05; and 16.7% vs. 6% p < 0.05, respectively. Adverse neonatal outcomes also differed significantly: HIE-TH had a higher rate of neonatal seizures 46.2% vs. 0% p < 0.001 and mortality 7.7% vs. 0% p < 0.001. CONCLUSIONS: Characteristic fetal monitoring pattern prior to delivery together with acute obstetric emergency events are associated with neonatal HIE, neurological morbidity, and mortality.

Association of MRI Brain Injury With Outcome After Pediatric Out-of-Hospital Cardiac Arrest.

OBJECTIVE: To determine the association between the extent of diffusion restriction and T2/fluid-attenuated inversion recovery (FLAIR) injury on brain MRI and outcomes after pediatric out-of-hospital cardiac arrest (OHCA). METHODS: Diffusion restriction and T2/FLAIR injury were described according to the pediatric MRI modification of the Alberta Stroke Program Early Computed Tomography Score (modsASPECTS) for children from 2005 to 2013 who had an MRI within 14 days of OHCA. The primary outcome was unfavorable neurologic outcome defined as ≥1 change in Pediatric Cerebral Performance Category (PCPC) from baseline resulting in a hospital discharge PCPC score 3, 4, 5, or 6. Patients with unfavorable outcomes were further categorized into alive with PCPC 3-5, dead due to withdrawal of life-sustaining therapies for poor neurologic prognosis (WLST-neuro), or dead by neurologic criteria. RESULTS: We evaluated MRI scans from 77 patients (median age 2.21 [interquartile range 0.44, 13.07] years) performed 4 (2, 6) days postarrest. Patients with unfavorable outcomes had more extensive diffusion restriction (median 7 [4, 10.3] vs 0 [0, 0] regions, p < 0.001) and T2/FLAIR injury (5.5 [2.3, 8.2] vs 0 [0, 0.75] regions, p < 0.001) compared to patients with favorable outcomes. Area under the receiver operating characteristic curve for the extent of diffusion restriction and unfavorable outcome was 0.96 (95% confidence interval [CI] 0.91, 0.99) and 0.92 (95% CI 0.85, 0.97) for T2/FLAIR injury. There was no difference in extent of diffusion restriction between patients who were alive with an unfavorable outcome and patients who died from WLST-neuro (p = 0.11). CONCLUSIONS: More extensive diffusion restriction and T2/FLAIR injury on the modsASPECTS score within the first 14 days after pediatric cardiac arrest was associated with unfavorable outcomes at hospital discharge.

Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is a leading cause of mortality and long-term neurological sequelae, affecting thousands of children worldwide. Current therapies to treat HIE are limited to cooling. Stem cell-based therapies offer a potential therapeutic approach to repair or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal trials. OBJECTIVES: To determine the efficacy and safety of stem cell-based interventions for the treatment of hypoxic-ischaemic encephalopathy (HIE) in newborn infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5), MEDLINE via PubMed (1966 to 8 June 2020), Embase (1980 to 8 June 2020), and CINAHL (1982 to 8 June 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing 1) stem cell-based interventions (any type) compared to control (placebo or no treatment); 2) use of mesenchymal stem/stromal cells (MSCs) of type (e.g. number of doses or passages) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus MSCs of other type or source; 3) use of stem cell-based interventions other than MSCs of type (e.g. mononuclear cells, oligodendrocyte progenitor cells, neural stem cells, hematopoietic stem cells, and inducible pluripotent stem cells) or source (e.g. autologous versus allogeneic, or bone marrow versus cord) versus stem cell-based interventions other than MSCs of other type or source; or 4) MSCs versus stem cell-based interventions other than MSCs. DATA COLLECTION AND ANALYSIS: For each of the included trials, two authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs or other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, death or major neurodevelopmental disability assessed at 18 to 24 months of age. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: Our search strategy yielded 616 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. Fifteen RCTs are currently registered and ongoing. We describe the three studies we excluded. AUTHORS' CONCLUSIONS: There is currently no evidence from randomised trials that assesses the benefit or harms of stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants.

Topiramate for hypoxic ischemic encephalopathy: A systematic review protocol.

BACKGROUND: Hypoxic ischemic encephalopathy (HIE) is brain injury caused by different reasons and the most common diagnosed is neonatal HIE. Most of the existing treatments have their own shortcomings or there are still some unexplained mechanisms in it. Topiramate (TPM) is a new drug for the treatment for seizures in neonates with HIE, but is currently used off-label. Our protocol aims to access the efficiency and safety of TPM for HIE. METHODS AND ANALYSIS: Eight databases will be searched by 2 independent researchers for the article on the topic of using TPM as treatment for HIE, including PubMed, the Cochrane Central Register of Controlled Trials (Cochrane Library), Embase, and Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wang Fang Database and Chinese Science and Technology Periodical database (VIP). The included papers are those published from the established date of the databases to 2019. The therapeutic effects based on the grade of neonatal behavioral neurological assessment will be regarded as the primary outcomes. RevMan V5.3 will be used to compute the data synthesis and carry out meta-analysis. The risk of bias will be appraised by the Cochrane risk of bias tool. Rare ratio for dichotomous outcomes and mean different for continuous data will be expressed with 95% confidence intervals (CI) for analysis. A random effects model or a fixed effects model will be employed, when heterogeneity is found or not. Subgroup analysis and sensitivity analysis will be applied if the heterogeneity is obvious. RESULTS: This study will provide the recent evidence of TPM for HIE from reducing seizure acticity. CONCLUSION: The conclusion of this study will provide proof to evaluate if TPM is effective and safe in the treatment of HIE.PROSPERO registration number: PROSPERO CRD42018117981.

Neonates with hypoxic-ischemic encephalopathy treated with hypothermia: Observations in a large Canadian population and determinants of death and/or brain injury.

BACKGROUND: Birth asphyxia in term neonates remains a serious condition that causes significant mortality and long-term neurodevelopmental sequelae despite hypothermia treatment. The objective of this study was to review therapeutic hypothermia practices in a large population of neonates with hypoxic-ischemic encephalopathy (HIE) across Canada and to identify determinants of adverse outcome. METHODS: Our retrospective observational cohort study examined neonates≥36 weeks, admitted to the Canadian Neonatal Network NICUs between 2010 and 2014, diagnosed with HIE, and treated with hypothermia. Adverse outcome was defined as death and/or brain injury. Maternal, birth, and postnatal characteristics were compared between neonates with adverse outcome and those without. The association between the variables which were significantly different (p < 0.05) between the two groups and adverse outcome were further tested, while adjusting for gestational age, birth weight, gender, and initial severity of encephalopathy. RESULTS: A total of 2187 neonates were admitted for HIE; 52% were treated with hypothermia and 40% developed adverse outcome. Initial severity of encephalopathy (moderate, p = 0.006; severe, p < 0.0001), hypotension treated with inotropes (p = 0.001), and renal failure (p = 0.007) were significantly associated with an increased risk of death and/or brain injury. CONCLUSIONS: In asphyxiated neonates treated with hypothermia, not only their initial severity of encephalopathy on admission, but also their cardiac and renal complications during the first days after birth were significantly associated with risk of death and/or brain injury. Careful monitoring and cautious management of these complications is warranted.

[Impact of hypoxic-ischemic injury on brain development in neonatal rats of different sexes].

Objective: To investigate the impact of hypoxic-ischemic brain injury (HIBI) on brain development in neonatal rats of different sexes. Methods: From January 1 to December 31, 2018, 60 7-day-old SD rats were randomly divided into HIBI-F group (20 rats), HIBI-M group (20 rats), and control group (20 rats, 10 females and 10 males). The animal model of HIBI was established with Rice-Vannucci method, with the rats' left common carotid artery double-ligated and severed. The rats were then placed in an incubator and exposed to a hypoxic gas mixture (8% O(2), 92% N(2)) for 90 minutes. No intervention was given to the control group. Two weeks after HIBI, the motor development was evaluated by footprint analysis, the residual brain volume was measured by brain magnetic resonance imaging (MRI), and the damage of synaptic ultra structure was analyzed by transmission electron microscope. One-way ANOVA or χ(2) test was used for inter-group statistical analysis, and paired sample t test was used to compare the bilateral step length and toe distance of rats in the same group. Results: The mortality rate of HIBI-F was significantly higher than that of HIBI-M (20%(4/20) vs. 10%(2/20), χ(2)=40.000, P=0.001). The right step length and toe distance in HIBI-M group and HIBI-F group were significantly shorter than those in control group ((7.5±0.3) cm and (7.9±0.5) cm vs. (8.2±0.5) cm, F=9.605, P<0.01, (0.9±0.1) cm and (1.0±0.0) cm vs. (1.1±0.1) cm, F=71.437, P<0.01). Besides, according to above data, the right step length and toe distance in HIBI-M group were significantly shorter than those in the HIBI-F group (both P<0.01). Furthermore, the right step length was significantly shorter than the left step length ((8.3±0.4) and (8.3±0.5) cm, t=5.289 and 10.580, P=0.001 and 0.010, respectively) and toe distance ((1.1±0.1) and (1.1±0.1) cm, t=7.953 and 6.435, respectively, both P<0.01) in both HIBI-M group and HIBI-F group. Similarly, the synaptic gap of the left precentral gyrus neurons was longer in HIBI-M group and HIBI-F group than that in control group ((23.4±1.3) and (19.7±1.6) nm vs. (18.9±0.6) nm, F=71.719, P<0.01), and also longer in HIBI-M group than that in HIBI-F group (t=7.645, P<0.01). Likewise, the residual brain volume in HIBI-M group and HIBI-F group was significantly less than that in control group ((67±4)% and (75±5)% vs. 100%, F=406.122, P<0.01), and the residual brain volume in HIBI-M group was significantly less than that in HIBI-F group (t=-5.281, P<0.01). Conclusions: Male neonatal rats are more vulnerable to HIBI and have severer subsequent brain injury and hemiplegia. Different treatment strategies for HIBI patients of different sexes should be developed.

Fifteen-minute consultation: Therapeutic hypothermia for infants with hypoxic ischaemic encephalopathy-translating jargon, prognosis and uncertainty for parents.

Hypoxic ischaemic encephalopathy may lead to death or severe long-term morbidity. Therapeutic hypothermia (TH) increases survival without impairments in childhood, but prognostic uncertainty may remain for years after birth. Clear and accurate communication is imperative but challenging. This article explores the predictive value of routinely performed assessments during TH, as well as the qualitative research relating to parental experience. This article will benefit paediatric trainees, consultants and nurse practitioners in providing: (1) the background information needed for initiating a conversation with parents regarding outcome and (2) optimising their communication with parents in translating jargon, prognosis and uncertainty.

Outcomes related to 10-min Apgar scores of zero in Japan.

OBJECTIVE: Apgar scores of zero at 10 min strongly predict mortality and morbidity in infants. However, recent data reported improved outcomes among infants with Apgar scores of zero at 10 min. We aimed to review the mortality rate and neurodevelopmental outcomes of infants with Apgar scores of zero at 10 min in Japan. DESIGN: Observational study. PATIENTS: Twenty-eight of 768 infants registered in the Baby Cooling Registry of Japan between 2012 and 2016, at >34 weeks' gestation, with Apgar scores of zero at 10 min who were treated with therapeutic hypothermia. INTERVENTIONS: We investigated the time of first heartbeat detection in infants with favourable outcomes and who had neurodevelopmental impairments or died. MAIN OUTCOME MEASURES: Clinical characteristics, mortality rate and neurodevelopmental outcomes at 18-22 months of age were evaluated. RESULTS: Nine (32%) of the 28 infants died before 18 months of age; 16 (57%) survived, but with severe disabilities and 3 (11%) survived without moderate-to-severe disabilities. At 20 min after birth, 14 of 27 infants (52%) did not have a first heartbeat, 13 of them died or had severe disabilities and one infant, who had the first heartbeat at 20 min, survived without disability. CONCLUSION: Our study adds to the recent evidence that neurodevelopmental outcomes among infants with Apgar scores of zero at 10 min may not be uniformly poor. However, in our study, all infants with their first heartbeat after 20 min of age died or had severe disabilities.

Outcome and Feasibility after 7 Years of Therapeutic Hypothermia in Southern Brazil.

OBJECTIVE: This study aimed to describe the experience with a protocol of therapeutic hypothermia (TH) in southern Brazil. STUDY DESIGN: Newborns with gestational age > 35 weeks with evidence of perinatal asphyxia plus moderate or severe encephalopathy were recruited between March 2011 and November 2017. Whole-body hypothermia for 72 hours, starting within the first 6 hours of life was used. Survivors underwent magnetic resonance imaging (MRI) and electroencephalogram (EEG). The primary outcome was death during hospitalization and neurodevelopment assessed using the Bayley Scales of Infant Development III (BSID III) at 12 months of age. RESULTS: A total of 72 newborns were treated (41 with moderate encephalopathy and 31 with severe encephalopathy), of whom 16 died. MRI was performed in 56 patients, and 24 presented some alterations. Fifty-three patients had an EEG: 11 normal, 20 mildly altered, 12 moderately altered, and 10 severely altered. Forty patients were evaluated through BSID III: 45% presented with some delay in neurodevelopment, 8 (20%) had motor retardation, 15 (37.5%) had language delay, and 13 (32.5%) had a delay in cognitive development. CONCLUSION: Mortality and adverse events were similar to those described in large randomized controlled trials. TH is a safe and an effective method of neurologic protection in asphyxiated newborns in a developing country when performed adequately.