Therapeutic hypothermia (TH) is the only treatment method that is known to reduce mortality and neurological sequela rates in newborns with moderate and severe hypoxic-ischemic encephalopathy (HIE). We aimed to evaluate the relationship between rectal temperatures measured upon arrival to our unit and short-term outcomes in newborns with HIE/TH. This was a retrospective study conducted between January 2022 and January 2023. The neonates were divided into three groups according to their rectal temperatures measured upon arrival at our unit as follows: Group 1) <33°C, Group 2) 33-34°C (group arriving at target temperature), and Group 3) >34°C. Short-term outcomes and mortality were compared between the groups. Group 1 consisted of 17 (19.8%) neonates, Group 2 consisted of 34 (39.5%) neonates, and Group 3 consisted of 35 (40.7%) neonates who had HIE and an indication for TH. Rectal temperature on arrival to the unit was not related to the rate of clinical convulsions, rates of abnormal attenuated electroencephalography and magnetic resonance imaging findings, rate of pulmonary hypertension, duration of mechanical ventilation and length of hospital stay. Although the mortality rate was 29% in Group 1, it was 3% and 6% in Groups 2 and 3, respectively (p = 0.016). No relationship was found between the rectal temperature upon arrival to the NICU and the short-term outcomes in HIE/TH neonates. However, the mortality rate in those who were overcooled was significantly higher compared with the other groups.

Neonatal outcomes following perinatal asphyxia vary significantly between low- and middle-income countries (LMICs) and high-income settings. Near-infrared spectroscopy is a non-invasive method for monitoring regional cerebral oxygen saturation (rScO2), providing real-time insights into brain oxygenation. In LMICs, where healthcare resources are limited, early rScO2 monitoring during therapeutic hypothermia (TH) may support neurological risk stratification. This study aimed to evaluate the association between early rScO2 levels and brain MRI abnormalities in asphyxiated neonates during their first week of life.

A retrospective longitudinal study was conducted on term neonates with moderate-to-severe perinatal asphyxia undergoing TH at a high-complexity healthcare institution in an LMIC. Continuous rScO2 monitoring was performed for 72 hours during cooling and rewarming. Values were analysed at 6-hour intervals. The primary outcome was abnormal brain MRI findings during the first week, defined as radiological injury to the basal ganglia, thalami, cortical/watershed areas, white matter or vascular territories. Logistic regression was used to assess the association between rScO2 and MRI abnormalities, and receiver operating characteristic analysis was used to evaluate predictive performance.

88 neonates were included, of which 29 had abnormal MRI findings. All patients were referred from lower-complexity centres. Elevated rScO2 in the first 6 hours was significantly associated with abnormal MRI findings (adjusted OR, 1.10; 95% CI 1.02 to 1.18). The rScO2 threshold showed limited sensitivity and moderate specificity.

Higher rScO₂ values during the first 6 hours of TH were associated with abnormal brain MRI findings. Although not definitive, early rScO2 monitoring may aid in identifying neonates at risk of neurological injury in LMICs.

Ethnic and racial disparities in neonatal outcomes have been well-documented, including higher risk of hypoxic-ischemic encephalopathy (HIE). Therapeutic hypothermia (TH) is the only approved treatment for infants with moderate to severe HIE and previous studies have shown mixed results regarding the impact of timing of initiation of TH on outcomes. These studies often include both inborn and outborn neonates and few minority patients.

This retrospective cohort study of exclusively inborn neonates from a high-volume, urban, safety net hospital (SNH) serving primarily racial/ethnic minority patients assessed the impact of timing of initiation of TH on short-term outcomes.

There were 268 infants diagnosed with moderate or severe HIE from 2009 to 2023. After excluding patients for late cooling (n = 32), participation in a clinical trial (n = 41), and major comorbidities (n = 8), there were 187 patients for analysis. Similar to our neonatal population, this study cohort consisted of 94 % racial/ethnic minority patients. The average time to initiate TH was 4.4 ± 1.1 h of life (HOL) and 88 % of qualifying neonates received TH by 6 HOL. Those initiating TH at <4 HOL compared to 4-6 HOL were more likely to have severe HIE (p = 0.01). The adjusted OR for the primary outcome of in-hospital death was not associated with timing of initiation of TH [aOR = 0.75 (95 % CI 0.40-1.33); p = 0.33], nor were secondary outcomes of abnormal brain MRI or length of stay.

In a vulnerable population from a high-volume SNH, timing of initiation of TH was not associated with short-term outcomes.

To validate a hypoxic ischaemic encephalopathy (HIE) prediction algorithm to identify infants at risk of HIE immediately after birth using readily available clinical data.

Secondary review of electronic health record data of term deliveries from January 2017 to December 2021.

A tertiary maternity hospital.

Infants >36 weeks' gestation with the following clinical variables available: Apgar Score at 1 min and 5 min, postnatal pH, base deficit, and lactate values taken within 1 hour of birth INTERVENTIONS: Previously trained open-source logistic regression and random forest (RF) prediction algorithms were used to calculate a probability index (PI) for each infant for the occurrence of HIE.

Validation of a machine learning algorithm to identify infants at risk of HIE in the immediate postnatal period.

1081 had a complete data set available within 1 hour of birth: 76 (6.95%) with HIE and 1005 non-HIE. Of the 76 infants with HIE, 37 were classified as mild, 29 moderate and 10 severe. The best overall accuracy was seen with the RF model. Median (IQR) PI in the HIE group was 0.70 (0.53-0.86) vs 0.05 (0.02-0.15), (p<0.001) in the non-HIE group. The area under the receiver operating characteristics curve for prediction of HIE=0.926 (0.893-0.959, p<0.001). Using a PI cut-off to optimise sensitivity of 0.30, 936 of the 1081 (86.5%) infants were correctly classified.

In a large unseen data set an open-source algorithm could identify infants at risk of HIE in the immediate postnatal period. This may aid focused clinical examination, transfer to tertiary care (if necessary) and timely intervention.

We aimed to determine if the implementation of teleconsults in the community hospital would decrease the time to initiation of therapeutic hypothermia (TH).We compared neonates treated with TH prior to implementation of the teleconsult program (pretele) to those treated after (posttele) for the outcomes of time to initiation of TH, seizures, and death/severe injury on brain MRI. We controlled for confounders using multivariable linear and logistic regression models.There were 52 pretele neonates and 49 posttele who were all born in community hospitals and treated with TH. Mothers in the posttele group were older and had higher rates of gestational diabetes. Fewer neonates with mild encephalopathy were cooled in the posttele period (13 [25.0%] pretele vs. 2 [4.1%] posttele). After controlling for gestational diabetes, maternal age, and severity of encephalopathy, there was no difference in time to TH initiation (p = 0.445), brain injury or death (p = 0.136), or seizure (p = 0.433) between the pre-and posttele groups. In the sub-analysis of the posttele group, the time to initiation was 4.50 hours (3.75, 5.00) for those with teleconsults versus 3.25 (2.12, 4.00) hours (p = 0.007) for those without.When comparing pre- to posttele groups, teleconsults in the community hospital did not significantly change the time to initiate TH or result in more adverse short-term outcomes of seizures or death/brain injury. In the sub-analysis of the posttele group, teleconsults did result in delayed initiation of TH but also possibly improved patient selection with fewer mildly encephalopathic neonates treated. · Telemedicine did not reduce the time to initiate TH.. · Fewer mild NE neonates received TH posttele.. · Multiple NE exams increased for the posttele group.. · No short-term adverse outcome differences were found..

To investigate the safety and efficacy of servo-controlled cooling during the transport of neonates with perinatal asphyxia.

We conducted a retrospective non-randomized case-control study at a single-center,which included 65 neonates diagnosed with Hypoxic-Ischemic Encephalopathy (HIE). These neonates were referred by the Shenzhen Children's Hospital medical transport team between January 2020 and June 2024. All subjects received 72 h of mild hypothermia treatment upon admission. Participants were categorized into an active group and a control group based on the use of servo-controlled cooling during transport. To evaluate differences in clinical characteristics, transport variables, and hospitalization outcomes between the two groups, we employed independent samples t-tests, Mann-Whitney U tests, and χ 2 tests for inter-group comparison.

Among the 65 subjects, there were 42 males and 23 females. The active group comprised 17 patients, while the control group included 48. No statistically significant differences were observed in sex, gestational age, birth weight, or HIE grade between the two groups (P > 0.05). In comparison to the control group, the active group experienced a shorter duration from leaving the referral center to reaching the target temperature (1 h vs. 2.67 h, Z = -4.513, P < 0.05), arrived at the treatment center at a lower temperature (34.03°C vs. 35.6°C, t = -4.991, P < 0.05), and demonstrated a higher proportion of patients within the target temperature range upon arrival [88.2% (15/17) vs. 16.7% (8/48), χ 2 = -0.774, P < 0.05]. Additionally, the length of hospitalization was shorter for the active group (15 days vs. 19 days, Z = -2.835, P < 0.05). The proportion of patients in the severe range on the aEEG recorded on the third day of cooling was higher in the control group [45.8% (22/48) vs. 11.8% (2/17), Z = -2.042, P < 0.05].

Active therapeutic hypothermia during transport is both safe and feasible.It enables a more rapid and stable achievement of the target temperature, enhances short-term EEG outcomes, and may serve as the preferred method for transporting neonates with hypoxic-ischemic encephalopathy(HIE).

There are divergent views and limited data regarding therapeutic hypothermia (TH) for neonatal hypoxic ischaemic encephalopathy (HIE) in sub-Saharan Africa (SSA). Our aim was to map and synthesize the published literature describing the use of TH for HIE in SSA, and the associated outcomes.

We searched Pubmed, Scopus, Google Scholar, and Web of Science from 1 January 1996 to 31 December 2023 for research studies, protocols, feasibility studies and surveys on term and near-term babies with HIE (population) treated with TH (concept) in SSA (context).

Thirty records were included: Three surveys, one feasibility study and 26 publications describing 23 studies of 21 cohorts, cooling 1420 babies in South Africa, Uganda, and Ghana. There were five studies recruiting at follow-up, five pilot studies, one randomised controlled trial, one case series, and 10 birth cohorts. The methods and design of the studies were highly variable and often inadequate. Only three studies with adequately described and validated cooling methods, non-selective sequential recruitment, and neurological outcomes were identified. Two studies of babies from birth, both with intensive care facilities, reported survival with normal/mildly abnormal outcome in 71% at discharge in one study, and 71% at 12 months in another, with 16% cerebral palsy (CP) in survivors, and only 16% loss to follow-up. The third study, which only included clinic attenders after TH without intensive care, reported 7% CP in survivors, but 36% loss to follow-up.

Data from the adequately described TH studies in SSA indicate outcomes at discharge and twelve months which are similar to global norms. However, these data are limited to South Africa. Interpretation of other studies was limited by loss to follow-up, variable methodology and exclusion of babies with severe HIE in some studies. There is a need for standardised definitions to facilitate interpretation in TH studies.

We hypothesized that outborn neonates from smaller birth volume hospitals would have more frequent adverse short-term outcomes following therapeutic hypothermia (TH).

Multicenter retrospective study comparing outcomes for small (<500 births/year), medium (501-1500 births/year), and large (>1500 births/year) hospitals in Northern New England. Multivariable logistic regression assessed the combined outcome of death/severe gray matter injury on MRI, controlling for encephalopathy severity and time to initiation of TH.

531 neonates were included from small (N=120), medium (N=193), and large (N=218) volume hospitals and TH was initiated at a median of 4.5, 4, and 2 hours of life respectively. The odds of the combined outcome were 4.3-fold higher in small versus large birth volume hospitals (95% CI = 1.6, 12.1, p=0.004), but not different in medium birth volume hospitals.

Neonates born in small volume hospitals had significantly higher odds of death or severe gray matter injury following TH.

Vasoactive inotrope score, renal score, fibrosis-5 index, and lactate-albumin ratio have not been investigated before in determining multiple organ dysfunctions accompanying infants with hypoxic-ischemic encephalopathy (HIE) in neonatal intensive care units (NICUs). The aim of this study was to determine whether multiple organ dysfunctions that may accompany HIE in infants are correlated with vasoactive inotrope score (VIS), renal score (RS), fibrosis-5 index (FIB-5), and lactate-albumin ratio (LAR), and whether these parameters can predict morbidity and mortality.

This is a retrospective study, and 106 newborns diagnosed with HIE and treated with hypothermia were included in the study. Vasoactive inotrope score for cardiac dysfunction, renal score for renal dysfunction, fibrosis-5 index, and lactate/albumin ratio for hepatic dysfunction were evaluated.

We found that the vasoactive inotrope score, renal score, fibrosis-5 index, and lactate-albumin ratio values of infants diagnosed with HIE are associated with cardiac, renal, and hepatic dysfunction. These values, calculated on the 2nd postnatal day, are particularly linked to prolonged hospital stay and mortality, which are key prognostic factors.

Our study is the first to combine vasoactive inotrope score, renal score, fibrosis-5 index, and lactate-albumin ratio parameters in determining organ dysfunction in newborns with hypoxic-ischemic encephalopathy and to reveal their prognostic and mortality prediction values. Therefore, although it offers new perspectives, new studies are needed.

The purpose of this paper is to compare the achievement of target temperature and the short-term neurological outcome according to the use of servo-controlled hypothermia in transport. This is a monocentric retrospective observational before-and-after uncontrolled study of newborns transported for neonatal encephalopathy. The first group was transported from 01/01/2019 to 12/31/2019 in passive hypothermia and the second group from 01/01/2021 to 12/31/2021 in controlled hypothermia. We included patients who had a total of 72 h of servo-controlled therapeutic hypothermia (CTH). We excluded those who had no or less than 72 h of CTH. There were 33 children transported in passive hypothermia in 2019 and 23 children transported in CTH in 2021. There were 9/28 (32%) patients in 2019 who reached the target temperature on arrival at the NICU compared with 20/20 (100%) in 2021 (p value < 0.01). There was a trend towards earlier age of therapeutic hypothermia if started in transport: 3.1 h ± 1.0 vs 4.0 h ± 2.4 for passive hypothermia (p value 0.07). There was no difference in age of arrival in NICU (4.0 h ± 1.2 with CTH vs 3.8 h ± 2.2 without CTH). We found no difference in short-term outcome (survival, abnormal MRI, seizures on EEG) between the two groups.

The use of servo-controlled therapeutic hypothermia makes it possible to reach the temperature target, without increasing the age of arrival in the NICU.

• CTH is rarely used during transport in France even if passive hypothermia rarely reaches temperature target, inducing overcooling and hyperthermia.

• This study shows better temperature control on arrival in the NICU with CTH compared to passive hypothermia, with no increase in arrival time.

Early induced therapeutic hypothermia represents the cornerstone treatment in neonates with probable hypoxic-ischemic encephalopathy. The selection of patients for treatment usually involves meeting criteria indicating evidence of perinatal hypoxia-ischemia and the presence of moderate or severe encephalopathy. In this review, we highlight the variability that exists between some of the different regional and national eligibility guidelines. Determining the potential presence of perinatal hypoxia-ischemia may require either one, two or three signs amongst history of acute perinatal event, prolonged resuscitation at delivery, abnormal blood gases and low Apgar score, with a range of cutoff values. Clinical neurological exams often define the severity of encephalopathy differently, with varying number of domains required for determining eligibility and blurred interpretation of findings assigned to different severity grades in different systems. The role of early electrophysiological assessment is weighted differently. A clinical implication is that infants may receive different care depending on the location in which they are born. This could also impact epidemiological data, as inference of rates of moderate-severe encephalopathy based on therapeutic hypothermia rates are misleading and influenced by different eligibility methods used. We would advocate that a universally endorsed single severity staging of encephalopathy is vital for standardizing management and neonatal outcome. IMPACT: Variability exists between regional and national therapeutic hypothermia eligibility guidelines for neonates with probable hypoxic-ischemic encephalopathy. Differences are common in both criteria indicating perinatal hypoxia-ischemia and criteria defining moderate or severe encephalopathy. The role of early electrophysiological assessment is also weighted unequally. This reflects in different individual care and impacts research data. A universally endorsed single severity staging of encephalopathy would be crucial for standardizing management.

Umbilical artery gas results help obstetricians assess fetal well-being during labor and guide screening decisions on eligibility for therapeutic hypothermia (ie, whole-body or head cooling). The accuracy of results, especially for the base deficit on arterial cord gas analysis, in predicting brain injury is questioned. A novel biomarker specifically calculated for fetal acid-base physiology and response to asphyxia-neonatal eucapnic pH as a marker of neonatal metabolic acidosis-has the potential to be an accurate predictor of hypoxic-ischemic encephalopathy.

We aimed to compare false-negative rates of hypoxic-ischemic encephalopathy for umbilical artery pH, base deficit, and neonatal eucapnic pH in assessing fetal acid-base balance as a marker of fetal well-being and predicting acute brain injury.

This is a retrospective single-center cohort study of newborns ≥ 35 weeks of gestation diagnosed with hypoxic-ischemic encephalopathy. We compared false-negative rates for any grade of hypoxic-ischemic encephalopathy using unilateral paired chi-square statistical analysis based on cutoff values for umbilical artery pH ≤7.00, base deficit ≥16 mmol/L, base deficit ≥12 mmol/L and neonatal eucapnic pH ≤7.14. We performed an analysis of variance between umbilical artery pH, base deficit, and neonatal eucapnic pH for each hypoxic-ischemic encephalopathy grade.

We included 113 newborns. False-negative rate for hypoxic-ischemic encephalopathy was significantly higher for base deficit <16 mmol/L (n=78/113; 69.0%) than <12 mmol/L (n=46/113; 40.7%), pH >7.00 (n=41/113; 36.3%), or neonatal eucpanic pH >7.14 (n=35/113; 31.0%) (P<.0001). All true-positive cases were identified using only umbilical artery pH and neonatal eucapnic pH. Base deficit ≥16 or ≥12 mmol/L did not add any value in identifying newborns with hypoxic-ischemic encephalopathy when using umbilical artery pH and neonatal eucapnic pH. No association emerged between any marker and hypoxic-ischemic encephalopathy severity grading.

Our findings support the accuracy of neonatal eucapnic pH to assess fetal well-being during labor and to improve predictive performance for acute brain injury. Neonatal eucpanic pH, in addition to umbilical artery pH, may be a viable alternative in identifying newborns at risk for hypoxic-ischemic encephalopathy.

Therapeutic hypothermia (TH) is the only currently approved treatment for neonatal hypoxic-ischemic encephalopathy (HIE) and must be started within 6 hours to optimize effectiveness. This narrow therapeutic window often requires initiation of TH before or during transport. The goal of this study was to assess the effects of servo-controlled TH versus passive hypothermia during transport on short-term outcomes in newborns with HIE. This was a single-center retrospective case-control study of neonates with HIE treated with active or passive TH during transport. Primary outcomes included brain injury on magnetic resonance imaging (MRI) and presence of seizures. Seventy-six neonates were included-13 active and 63 passive. The active TH group was more likely to arrive within goal temperature. No difference was noted between groups in seizures or TH complications. Active TH was associated with increased injury on MRI. Active TH resulted in tighter temperature control, but no improvement in short-term outcomes in our cohort. The MRI findings may be due to differences in overall disease severity, which could not be adjusted for, given the modest sample size.

In neonates with birth asphyxia (BA) and hypoxic-ischemic encephalopathy, therapeutic hypothermia (TH), initiated within six hours, is the only safe and established neuroprotective measure to prevent secondary brain injury. Infants born outside of TH centers have delayed access to cooling.

To compare in-hospital mortality, occurrence of seizures, and functional status at discharge in newborns with BA depending on postnatal transfer for treatment to another hospital within 24 h of admission (transferred (TN) versus non-transferred neonates (NTN)).

Nationwide retrospective cohort study from a comprehensive hospital dataset using codes of the International Classification of Diseases, 10th modification (ICD-10). Clinical and outcome information was retrieved from diagnostic and procedural codes. Hierarchical multilevel logistic regression modeling was performed to quantify the effect of being postnatally transferred on target outcomes.

All discharges from German hospitals from 2016 to 2021.

Full term neonates with birth asphyxia (ICD-10 code: P21) admitted to a pediatric department on their first day of life.

Postnatal transfer to a pediatric department within 24 h of admission to an external hospital.

In-hospital death; secondary outcomes: seizures and pediatric complex chronic conditions category (PCCC) ≥ 2.

Of 11,703,800 pediatric cases, 25,914 fulfilled the inclusion criteria. TNs had higher proportions of organ dysfunction, TH, organ replacement therapies, and neurological sequelae in spite of slightly lower proportions of maternal risk factors. In TNs, the adjusted odds ratios (OR) for death, seizures, and PCCC ≥ 2 were 4.08 ((95% confidence interval 3.41-4.89), 2.99 (2.65-3.38), and 1.76 (1.52-2.05), respectively. A subgroup analysis among infants receiving TH (n = 3,283) found less pronounced adjusted ORs for death (1.67 (1.29-2.17)) and seizures (1.26 (1.07-1.48)) and inverse effects for PCCC ≥ 2 (0.81 (0.64-1.02)) in TNs.

This comprehensive nationwide study found increased odds for adverse outcomes in neonates with BA who were transferred to another facility within 24 h of hospital admission. Closely linking obstetrical units to a pediatric department and balancing geographical coverage of different levels of care facilities might help to minimize risks for postnatal emergency transfer and optimize perinatal care.

Clinical trials of hypothermia after pediatric cardiac arrest (CA) have not seen robust improvement in functional outcome, possibly because of the long delay in achieving target temperature. Previous work in infant piglets showed that high nasal airflow, which induces evaporative cooling in the nasal mucosa, reduced regional brain temperature uniformly in half the time needed to reduce body temperature. Here, we evaluated whether initiation of hypothermia with high transnasal airflow provides neuroprotection without adverse effects in the setting of asphyxic CA. Anesthetized piglets underwent sham-operated procedures (n = 7) or asphyxic CA with normothermic recovery (38.5°C; n = 9) or hypothermia initiated by surface cooling at 10 (n = 8) or 120 (n = 7) min or transnasal cooling initiated at 10 (n = 7) or 120 (n = 7) min after resuscitation. Hypothermia was sustained at 34°C with surface cooling until 20 h followed by 6 h of rewarming. At 4 days of recovery, significant neuronal loss occurred in putamen and sensorimotor cortex. Transnasal cooling initiated at 10 min significantly rescued the number of viable neurons in putamen, whereas levels in putamen in other hypothermic groups remained less than sham levels. In sensorimotor cortex, neuronal viability in the four hypothermic groups was not significantly different from the sham group. These results demonstrate that early initiation of high transnasal airflow in a pediatric CA model is effective in protecting vulnerable brain regions. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field or emergency room for early initiation of brain cooling after pediatric CA.NEW & NOTEWORTHY The onset of therapeutic hypothermia after cardiac resuscitation is often delayed, leading to incomplete neuroprotection. In an infant swine model of asphyxic cardiac arrest, initiation of high transnasal airflow to maximize nasal evaporative cooling produced hypothermia sufficient to provide neuroprotection that was not inferior to body surface cooling. Because of its simplicity and portability, this technique may be of use in the field or emergency room for rapid brain cooling in pediatric cardiac arrest victims.

To determine the effectiveness of phase-change-material mattress (PCM) during transportation of newborns with hypoxic ischemic encephalopathy (HIE).

Randomized controlled trial of newborns with HIE from June 2016 to December 2019. Patients were randomized to transport with PCM or without PCM (control) when transferred to a cooling center in northern Vietnam. Primary outcome measure was mortality rate, secondary outcomes including temperature control and adverse effects.

Fifty-Two patients in PCM-group and 61 in control group. Median rectal temperature upon arrival was 34.5 °C (IQR 33.5-34.8) in PCM-group and 35.1 °C (IQR 34.5-35.9) in control group (p = 0.023). Median time from birth to reach target temperature was 5.0 ± 1.4 h and 5.5 ± 1.2 h in the respective groups (p = 0.065). 81% of those transported with PCM versus 62% of infants transported without (p = 0.049) had reached target temperature within the 6-h timeframe. There was no record of overcooling (< 32 °C) in any of the groups. The was no difference in mortality rate between the two groups (33% and 34% respectively (p > 0.05)).

Phase-change-material can be used as a safe and effective cooling method during transportation of newborns with HIE in low-resource settings.

The study was retro-prospectively registered in Clinical Trials (04/05/2022, NCT05361473).

Therapeutic hypothermia is now standard of care for neonates with hypoxic-ischemic encephalopathy (HIE) in high income countries (HIC). Conversely, compelling trial evidence suggests that hypothermia is ineffective, and may be deleterious, in low- and middle-income countries (LMIC), likely reflecting the lower proportion of infants who had sentinel events at birth, suggesting that injury had advanced to a stage when hypothermia is no longer effective. Although hypothermia significantly reduced the risk of death and disability in HICs, many infants survived with disability and in principle may benefit from targeted add-on neuroprotective or neurorestorative therapies. The present review will assess biomarkers that could be used to personalize treatment for babies with HIE - to determine first whether an individual infant is likely to respond to hypothermia, and second, whether additional treatments may be beneficial.

Therapeutic hypothermia is the standard treatment for neonates with hypoxic-ischemic encephalopathy. Preclinical evidence indicates that the time to initiate therapeutic hypothermia correlates with its therapeutic success. This study aims to explore whether there is a correlation between the early initiation of therapeutic hypothermia and improved short-term neurological outcomes in cooled asphyxiated newborns.

A retrospective analysis was conducted, involving 68 neonates from two different neonatal intensive care units. The impact of time to initiate treatment, time to reach the target temperature, and time between initiation and target temperature was correlated with short-term outcomes on MRI.

We did not find a significant difference between outcomes regarding the time to start treatment and the time to achieve the target temperature. Interestingly, neonates with a poor outcome were treated on average earlier than neonates with a favorable outcome but required more time to reach the target temperature. Additionally, the study results did not support the hypothesis that a shorter time to initiate treatment would lead to shorter times to achieve the target temperature.

Based on our findings, it is recommended to prioritize a thorough evaluation of neonatal encephalopathy before initiating therapeutic hypothermia. Early initiation of treatment should be balanced with the time required for precise assessment to ensure better outcomes.

To consider the classical use of "pH < 7.0 and/or a base deficiency ≥12 mmol/L" as markers of the risk of neonatal hypoxic-ischemic encephalopathy (HIE), recalling various criticisms of the use of these markers in favor of that of neonatal eucapnic pH, which appears to be a better marker of this risk.

Fifty-five cases of acidemia with pH < 7.00 were collected from a cohort from the Nice University Hospital with eight cases of HIE. We compared the receiver operating characteristics curves established from the positive likelihood ratio (+LR) for each case of: umbilical cord artery pH (pHa), neonatal eucapnic pH (pH euc-n) in isolation (not matched to pHa), and matched pHa to its own pH euc-n.

The areas under the curve (AUC) are identical for pHa and pH euc-n, but AUC for the matched pair pHa-pH euc-n appears superior but non-significant because of the small number in our cohort. However, using the bootstrap method, the partial AUC for a sensitivity greater than 75% indicates the significant superiority (P < 0.01) of the matched pair pHa-pH euc-n approach.

The originality of this study lies in the use of two methodologic approaches: (1) standardized partial analysis of the AUCs of the pHa curve and that of pHa matched to its own pH euc-n, and (2) bootstrap statistical technique, that allowed us to conclude (P < 0.01) that the combined use of pH measured at the cord coupled with its eucapnic correction is better for diagnosing metabolic acidosis and best predicting the risk of HIE.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI).

We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes.

We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression.

Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.

Programs that aim to improve the detection hypoxic-ischemic encephalopathy (HIE) should establish which neonates suffering from perinatal asphyxia need to be monitored within the first 6 h of life.

An observational prospective cohort study of infants with gestational age ≥35 weeks, and above 1,800g, were included according to their arterial cord pH value (ApH): ≤7.00 vs. 7.01-7.10. Data was collected including obstetrical history, as well as neonatal comorbidities, including the presence of HIE, that happened within 6 h of life. A standardized neurological exam was performed at discharge.

There were 9,537 births; 176 infants with ApH 7.01-7.10 and 117 infants with ApH ≤7.00. All 9 cases with moderate-to-severe HIE occurred among infants with ApH ≤7.00. The incidence of global and moderate-severe HIE was 3/1,000 and 1/1,000 births, respectively. Outcome at discharge (abnormal exam or death) showed an OR 12.03 (95% CI 1.53, 94.96) in infants with ApH ≤7.00 compared to ApH 7.01-7.10 cohort. Ventilation support was 5.1 times (95% CI 2.87, 9.03) more likely to be needed by those with cord ApH ≤7.00 compared to those with ApH 7.01-7.10, as well as hypoglycemia (37% vs. 25%; p = 0.026). In 55%, hypoglycemia occurred despite oral and/or intravenous glucose administration had been already initiated.

Cord pH 7.00 might be a safe pH cut-off point when developing protocols to monitor infants born with acidemia in order to identify infants with moderate or severe HIE early on. There is non-negligible comorbidity in the ApH ≤7.00 cohort, but also in the 7.01-7.10 cohort.

To determine if time to reaching target temperature (TT) is associated with death or neurodevelopmental impairment (NDI) at 2 years of age in infants with hypoxic-ischemic encephalopathy (HIE).

Newborn infants ≥36 weeks of gestation diagnosed with moderate or severe HIE and treated with therapeutic hypothermia were stratified based on time at which TT was reached, defined as early (ie, ≤4 hours of age) or late (>4 hours of age). Primary outcomes were death or NDI. Secondary outcomes included neurodevelopmental assessment with Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at age 2.

Among 500 infants, the median time to reaching TT was 4.3 hours (IWR, 3.2-5.7 hours). Infants in early TT group (n = 211 [42%]) compared with the late TT group (n = 289 [58%]) were more likely to be inborn (23% vs 13%; P < .001) and have severe HIE (28% vs 19%; P = .03). The early and late TT groups did not differ in the primary outcome of death or any NDI (adjusted RR, 1.05; 95% CI, 0.85-0.30; P = .62). Among survivors, neurodevelopmental outcomes did not differ significantly in the 2 groups (adjusted mean difference in Bayley Scales of Infant Development-III scores: cognitive, -2.8 [95% CI, -6.1 to 0.5], language -3.3 [95% CI, -7.4 to 0.8], and motor -3.5 [95% CI, -7.3 to 0.3]).

In infants with HIE, time to reach TT is not independently associated with risk of death or NDI at age 2 years. Among survivors, developmental outcomes are similar between those who reached TT at <4 and ≥4 hours of age.

High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL); NCT02811263; https://beta.

gov/study/NCT02811263.

Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE.

Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics.

Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment.

We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS.

We have identified seven outcomes that should be measured and reported in all studies for the treatment of neonatal encephalopathy. Previously, a core outcome set for neonatal encephalopathy treatments did not exist. This will help to reduce heterogeneity in outcomes reported in clinical trials and other studies, and help researchers identify the best treatments for neonatal encephalopathy.

Predicting neurodevelopmental outcomes in hypoxic-ischaemic encephalopathy (HIE) remains imprecise, despite advanced imaging and neurophysiological tests. We explored the predictive value of socio-economic status (SES).

The cohort comprised 93 infants (59% male) with HIE, who had received therapeutic hypothermia. Patients underwent magnetic resonance imaging, and brain injuries were quantified using the Barkovich scoring system. Family SES was self-reported using a questionnaire. Adverse outcomes were defined as mild to severely delayed development with a score of ≤85 in any domain at 2 years of age, based on the Bayley Scales of Infant Development, Second Edition. Data are presented as odds ratios (OR) with 95% confidence intervals (95% CI).

Multiple regression modelling revealed that higher parental education was strongly associated with good cognitive development, when adjusted for gestational age, serum lactate and brain injuries (OR 2.20, 95% CI 1.16-4.36). The effect size of parental education (β = 0.786) was higher than one score for any brain injury using the Barkovich scoring system (β = -0.356). The literacy environment had a significant effect on cognitive development in the 21 infants who had brain injuries (OR 40, 95% CI 3.70-1352).

Parental education and the literacy environment influenced cognitive outcomes in patients with HIE.

Interdisciplinary fetal-neonatal neurology (FNN) training strengthens neonatal neurocritical care (NNCC) clinical decisions. Neonatal neurological phenotypes require immediate followed by sustained neuroprotective care path choices through discharge. Serial assessments during neonatal intensive care unit (NICU) rounds are supplemented by family conferences and didactic interactions. These encounters collectively contribute to optimal interventions yielding more accurate outcome predictions. Maternal-placental-fetal (MPF) triad disease pathways influence postnatal medical complications which potentially reduce effective interventions and negatively impact outcome. The science of uncertainty regarding each neonate's clinical status must consider timing and etiologies that are responsible for fetal and neonatal brain disorders. Shared clinical decisions among all stakeholders' balance "fast" (heuristic) and "slow" (analytic) thinking as more information is assessed regarding etiopathogenetic effects that impair the developmental neuroplasticity process. Two case vignettes stress the importance of FNN perspectives during NNCC that integrates this dual cognitive approach. Clinical care paths evaluations are discussed for an encephalopathic extremely preterm and full-term newborn. Recognition of cognitive errors followed by debiasing strategies can improve clinical decisions during NICU care. Re-evaluations with serial assessments of examination, imaging, placental-cord, and metabolic-genetic information improve clinical decisions that maintain accuracy for interventions and outcome predictions. Discharge planning includes shared decisions among all stakeholders when coordinating primary care, pediatric subspecialty, and early intervention participation. Prioritizing social determinants of healthcare during FNN training strengthens equitable career long NNCC clinical practice, education, and research goals. These perspectives contribute to a life course brain health capital strategy that will benefit all persons across each and successive lifespans.

Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects.

This manuscript reports on the establishment of the registry and the primary findings to date.

From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH.

The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work.

Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects.

The Swiss National Asphyxia and Cooling Register was implemented in 2011. This study assessed quality indicators of the cooling process and (short-term) outcomes of neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH) longitudinally over time in Switzerland. This is a multicenter national retrospective cohort study of prospectively collected register data. Quality indicators were defined for longitudinal comparison (2011-2014 vs. 2015-2018) of processes of TH and (short-term) outcomes of neonates with moderate-to-severe HIE. Five hundred seventy neonates receiving TH in 10 Swiss cooling centers were included (2011-2018). Four hundred forty-nine (449/570; 78.8%) neonates with moderate-to-severe HIE received TH according to the Swiss National Asphyxia and Cooling Register Protocol. Quality indicators of processes of TH improved in 2015-2018 (compared with 2011-2014): less passive cooling (p = 0.013), shorter time to reach target temperature (p = 0.002), and less over- or undercooling (p < 0.001). In 2015-2018, adherence to performing a cranial magnetic resonance imaging after rewarming improved (p < 0.001), whereas less cranial ultrasounds were performed on admission (p = 0.012). With regard to quality indicators of short-term outcomes, persistent pulmonary hypertension of the neonate was reduced (p = 0.003), and there was a trend toward less coagulopathy (p = 0.063) in 2015-2018. There was no statistically significant change in the remaining processes and outcomes. The Swiss National Asphyxia and Cooling Register is well implemented with good overall adherence to the treatment protocol. Management of TH improved longitudinally. Continuous reevaluation of register data is desirable for quality assessment, benchmarking, and maintaining international evidence-based quality standards.

Hypoxic ischemic encephalopathy (HIE) is one of the common causes of mortality and morbidity in newborns. Despite therapeutic hypothermia, an important treatment with proven efficacy, the morbidity and mortality rates remain high. The aim of this study was to neurodevelopmentally evaluate patients who underwent therapeutic hypothermia.

Included herein were patients who underwent hypothermia between 2018 and 2020. Their medical files were reviewed retrospectively, and their demographic and clinical information was recorded. Patients whose contact information was available were called to the developmental pediatrics outpatient clinic for a neurodevelopmental evaluation. The Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) was used as the evaluation tool. Laboratory values and clinical parameters of the patients were further analyzed.

It was found that 42 patients underwent hypothermia in 3 years, of whom 14 (33.3%) had died. Of the 28 patients who were discharged, 20 children could be reached, and a neurodevelopmental evaluation was performed. Developmental delay in the cognitive area was detected in 11 (55%) patients, delay in the language area was found in 9 (45%) patients, and delay in the motor area was found in 11 (55%) patients. The correlation and regression analysis results determined that the time to start cooling was the most effective common factor in all 3 fields of scoring.

The time to start cooling is related to the neurodevelopmental outcomes of patients with HIE. The earlier cooling is started, the better the neurodevelopmental results. Despite therapeutic hypothermia, the neurodevelopmental development of infants may be adversely affected. These patients should be followed-up neurodevelopmentally for a long time.

Neurologic outcome from out-of-hospital pediatric cardiac arrest remains poor. Although therapeutic hypothermia has been attempted in this patient population, a beneficial effect has yet to be demonstrated, possibly because of the delay in achieving target temperature. To minimize this delay, we developed a simple technique of transnasal cooling. Air at ambient temperature is passed through standard nasal cannula with an open mouth to produce evaporative cooling of the nasal passages. We evaluated efficacy of brain cooling with different airflows in different size piglets. Brain temperature decreased by 3°C within 25 minutes with nasal airflow rates of 16, 32, and 16 L/min in 1.8-, 4-, and 15-kg piglets, respectively, whereas rectal temperature lagged brain temperature. No substantial spatial temperature gradients were seen along the neuroaxis, suggesting that heat transfer is via blood convection. The evaporative cooling did not reduce nasal turbinate blood flow or sagittal sinus oxygenation. The rapid and selective brain cooling indicates a high humidifying capacity of the nasal turbinates is present early in life. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field for early initiation of brain cooling prior to maintenance with standard surface cooling after pediatric cardiac arrest.

To describe longitudinal motor development in children treated with therapeutic- hypothermia (TH) due to neonatal hypoxic-ischaemic encephalopathy (HIE) and to explore motor functioning in early adolescence.

Children treated with TH due to HIE during 2007-2009, in Stockholm, participated in a prospective follow-up study. Motor development was assessed on four occasions, reported as percentiles and at mean ages. Alberta Infant Motor Scale was used at 0.35 years of age, Bayley Scales of Infant and Toddler Development-III at 2.1 years and Movement Assessment Battery for Children (MABC-2) at 7.3 and 11.1 years of age. MABC-2 Checklist was completed by parents at 7.3 and 11.1 years of age. General cognition was assessed using Wechsler Intelligence Scales for Children Fifth Edition (WISC-V).

Thirty-one percent (14/45) of the children had a motor score ≤ 15th percentile, indicating risk of motor difficulties at 11.1 years of age, and simultaneously the scores from parents of 52% (23/44), indicating risk of motor difficulties in the everyday context. These children had significantly lower motor percentile at 2.1 years of age, but within the normal range. Longitudinal motor development displayed a weak association with WISC-V Full Scale IQ (rs0.38, p = 0.013).

Among survivors of hypothermia-treated HIE free of moderate/severe cerebral palsy, a third had MABC-2 scores indicating risk of motor difficulties at 11.1 years of age. As motor difficulties became more apparent over time, we suggest that children treated with TH due to neonatal HIE should be followed into at least middle school age.

Hypoxic-ischemic encephalopathy (HIE) and associated multiorgan injury are significant causes of morbidity and mortality in term and near-term neonates. Therapeutic hypothermia (TH) is the current standard of care for neuroprotection in neonates with HIE. In our experience, the majority of babies born with HIE were found in nontertiary care facilities in our region, where effective methods of cooling during transport to tertiary care centers are desirable. Most centers initiate passive TH at referral hospitals, while active cooling is typically initiated during transport. The objective of this study was to evaluate the effectiveness of three methods of cooling during transport of neonates with HIE in southern Alberta. In this prospective cohort study, 186 neonates with HIE were transported between January 2013 and December 2021. Among the 186 neonates, 47 were passively cooled, 36 actively cooled with gel packs, and 103 cooled with a servo-controlled cooling device. The clinical characteristics were comparable for the three groups, with no difference in adverse events. Fifteen neonates (8%) died and 54 neonates (29%) suffered radiologically determined brain injury. Servo-controlled cooling was found to be superior to other methods in maintaining a target temperature without significant fluctuation during transport and with temperature in the target range on arrival at tertiary care facilities. The rate of overcooling was also lower in the servo-controlled group compared with other groups. There were no statistically significant differences between the groups in relation to mortality and brain MRI changes associated with HIE. Adjusting for GA, 10-minute Apgar score, base excess, HIE stage, and need for intubation during transport, passive cooling increased the odds of temperature fluctuation outside the range by 12-fold and gel pack cooling by 13-fold compared with servo-controlled cooling. The use of servo-controlled TH devices should be the preferred practice wherever feasible. (REB17-1334_REN3).

Few reliable or easily obtainable biomarkers to predict long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) have been identified. We previously showed that mattress temperature (MT), as proxy for disturbed temperature regulation during therapeutic hypothermia (TH), predicts injury on early MRI and holds promise as physiologic biomarker. To determine whether MT in neonates treated with TH for moderate-severe HIE is associated with long-term outcome at 18-22 months, we performed a secondary analysis of the Optimizing Cooling trial using MT data from 167 infants treated at a core temperature of 33.5°C. Median MTs from four time-epochs (0-6 h, 6-24 h, 24-48 h, and 48-72 h of TH) were used to predict death or moderate-severe neurodevelopmental impairment (NDI), using epoch-specific derived and validated MT cutoffs. Median MT of infants who died or survived with NDI was consistently 1.5-3.0°C higher throughout TH. Infants requiring a median MT above the derived cut-offs had a significantly increased odds of death or NDI, most notably at 0-6 h (aOR 17.0, 95%CI 4.3-67.4). By contrast, infants who remained below cut-offs across all epochs had 100% NDI-free survival. MTs in neonates with moderate-severe HIE during TH are highly predictive of long-term outcome and can be used as physiologic biomarker.

Prenatal and perinatal care of pregnant mothers has been adversely affected during the COVID-19 pandemic. Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal death and long-term neurological disabilities. Therapeutic hypothermia is effective for neonatal HIE. This study evaluated the effect of the pandemic on neonatal HIE.

This retrospective single-center study compared neonatal HIE evaluation and hypothermia treatment between pre-COVID-19 pandemic (1 January 2018-31 December 2019) and COVID-19 pandemic (1 January 2020-31 December 2021) periods. Infants with abnormal neurological examination and or significant metabolic acidosis were admitted to NICU for evaluation of HIE and therapeutic hypothermia. Demographics, NICU admission and interventions, and neonatal outcomes were compared between infants born during the two periods using χ², t-test, and Wilcoxon rank-sum test as appropriate. Statistical Process Control charts show the yearly proportion of infants evaluated for HIE and those treated with therapeutic hypothermia.

From the pre-pandemic to the pandemic period, the proportion of infants that met HIE screening criteria increased from 13% to 16% (p < 0.0001), the proportion of infants admitted to NICU for HIE evaluation increased from 1% to 1.4% (p = 0.02), and the maternal hypertension rates of the admitted infants increased from 30% to 55% (p = 0.006). There was no difference in the proportions of the infants diagnosed with HIE (0.7% vs. 0.9%, p = 0.3) or treated with therapeutic hypothermia (0.2% vs. 0.3%, p = 0.3) between the two periods. There were no differences in the HIE severity and outcomes of the infants treated with therapeutic hypothermia between the two periods.

During the COVID-19 pandemic, we observed a significant increase in NICU admission for HIE evaluation. While we did not find significant increases in neonatal HIE and the need for therapeutic hypothermia, larger studies are needed for a comprehensive assessment of the impact of the COVID-19 pandemic on neonatal HIE.

Neonates requiring intensive care are in a critical period of brain development that coincides with the neonatal intensive care unit (NICU) hospitalization, placing these infants at high risk of brain injury and long-term neurodevelopmental impairment. Care in the NICU has the potential to be both harmful and protective to the developing brain. Neuro-focused quality improvement efforts address 3 main pillars of neuroprotective care: prevention of acquired injury, protection of normal maturation, and promotion of a positive environment. Despite challenges in measurement, many centers have shown success with consistent implementation of best and potentially better practices that may improve markers of brain health and neurodevelopment.

The peripheral immune system plays a critical role in neuroinflammation of the central nervous system after an insult. Hypoxic-ischemic encephalopathy (HIE) induces a strong neuroinflammatory response in neonates, which is often associated with exacerbated outcomes. In adult models of ischemic stroke, neutrophils infiltrate injured brain tissue immediately after an ischemic insult and aggravate inflammation via various mechanisms, including neutrophil extracellular trap (NETs) formation. In this study, we used a neonatal model of experimental hypoxic-ischemic (HI) brain injury and demonstrated that circulating neutrophils were rapidly activated in neonatal blood. We observed an increased infiltration of neutrophils in the brain after exposure to HI. After treatment with either normothermia (NT) or therapeutic hypothermia (TH), we observed a significantly enhanced expression level of the NETosis marker Citrullinated H3 (Cit-H3), which was significantly more pronounced in animals treated with TH than in those treated with NT. NETs and NLR family pyrin domain containing 3 (NLRP-3) inflammasome assembly are closely linked in adult models of ischemic brain injury. In this study, we observed an increase in the activation of the NLRP-3 inflammasome at the time points analyzed, particularly immediately after TH, when we observed a significant increase in NETs structures in the brain. Together, these results suggest the important pathological functions of early arriving neutrophils and NETosis following neonatal HI, particularly after TH treatment, which is a promising starting point for the development of potential new therapeutic targets for neonatal HIE.

The Brain is vulnerable to numerous insults that can act in the pre-, peri-, and post-natal period. There is growing evidence that demonstrate how oxidative stress (OS) could represent the final common pathway of all these insults. Fetuses and newborns are particularly vulnerable to OS due to their inability to active the antioxidant defenses. Specific molecules involved in OS could be measured in biologic fluids as early biomarkers of neonatal brain injury with an essential role in neuroprotection. Although S-100B seems to be the most studied biomarker, its use in clinical practice is limited by the complexity of brain damage etiopathogenesis and the time of blood sampling in relation to the brain injury. Reliable early specific serum markers are currently lacking in clinical practice. It is essential to determine if there are specific biomarkers that can help caregivers to monitor the progression of the disease in order to active an early neuroprotective strategy. We aimed to describe, in an educational review, the actual evidence on serum biomarkers for the early identification of newborns at a high risk of neurological diseases. To move the biomarkers from the bench to the bedside, the assays must be not only be of a high sensitivity but suitable for the very rapid processing and return of the results for the clinical practice to act on. For the best prognosis, more studies should focus on the association of these biomarkers to the type and severity of perinatal brain damage.

Therapeutic hypothermia (TH) commenced soon after birth for neonatal hypoxic ischaemic encephalopathy (HIE) improves survival and reduces neurodisability. Availability of active TH at the place of birth (Immediate-TH) in the UK is unknown.

Population-based observational study.

UK maternity centres.

5 975 056 births from 2011 to 2018.

For each maternity centre, the year active Immediate-TH was available and the annual birth rates were established. Admission temperatures of infants with HIE transferred from non-tertiary centres with and without Immediate-TH were compared.

Quantify the annual number of births with access to Immediate-TH. Secondary outcomes included temporal changes in Immediate-TH and admission temperatures for infants requiring transfer to tertiary centres.

In UK maternity centres, 75 of 194 (38.7%) provided Immediate-TH in 2011 rising to 95 of 192 (49.5%, p=0.003) in 2018 with marked regional variations. In 2011, 394 842 (51.2%) of 771 176 births had no access to Immediate-TH compared with 276 258 (39.3%) of 702 794 births in 2018 (p<0.001). More infants with HIE arrived in the therapeutic temperature range (76.5% vs 67.3%; OR 1.58, 95% CI 1.25 to 2.0, p<0.001) with less overcooling (10.6% vs 14.3%; OR 0.71, 95% CI 0.51 to 0.98, p=0.036) from centres with Immediate-TH compared with those without.

Availability of active Immediate-TH has slowly increased although many newborns still have no access and rely on transport team arrival to commence active TH. This is associated with delayed optimal hypothermic management. Provision of Immediate-TH across all units, with appropriate training and support, could improve care of infants with HIE.

Therapeutic hypothermia (TH) is the standard treatment for neonatal hypoxia-ischemia (HI) with a time window limited up to 6 h post injury. However, influence of sexual dimorphism in the therapeutic window for TH has not yet been elucidated in animal models of HI. Therefore, the aim of this study was to investigate the most effective time window to start TH in male and female rats submitted to neonatal HI. Wistar rats (P7) were divided into the following groups: NAÏVE and SHAM (control groups), HI (submitted to HI) and TH (submitted to HI and TH; 32ºC for 5 h). TH was started at 2 h (TH-2 h group), 4 h (TH-4 h group), or 6 h (TH-6 h group) after HI. At P14, animals were subjected to behavioural tests, volume of lesion and reactive astrogliosis assessments. Male and female rats from the TH-2 h group showed reduction in the latency of behavioral tests, and decrease in volume of lesion and intensity of GFAP immunofluorescence. TH-2 h females also showed reduction of degenerative cells and morphological changes in astrocytes. Interestingly, females from the TH-6 h group showed an increase in volume of lesion and in number of degenerative hippocampal cells, associated with worse behavioral performance. Together, these results indicate that TH neuroprotection is time- and sex-dependent. Moreover, TH started later (6 h) can worsen volume of brain lesion in females. These data indicate the need to develop specific therapeutic protocols for each sex and reinforce the importance of early onset of the hypothermic treatment.