Whole-Body Hypothermia vs Targeted Normothermia for Neonates With Mild Encephalopathy: A Multicenter Pilot Randomized Clinical Trial.

Importance: Although whole-body hypothermia is widely used after mild neonatal hypoxic-ischemic encephalopathy (HIE), safety and efficacy have not been evaluated in randomized clinical trials (RCTs), to our knowledge. Objective: To examine the effect of 48 and 72 hours of whole-body hypothermia after mild HIE on cerebral magnetic resonance (MR) biomarkers. Design, Setting, and Participants: This open-label, 3-arm RCT was conducted between October 31, 2019, and April 28, 2023, with masked outcome analysis. Participants were neonates at 6 tertiary neonatal intensive care units in the UK and Italy born at or after 36 weeks' gestation with severe birth acidosis, requiring continued resuscitation, or with an Apgar score less than 6 at 10 minutes after birth and with evidence of mild HIE on modified Sarnat staging. Statistical analysis was per intention to treat. Interventions: Random allocation to 1 of 3 groups (1:1:1) based on age: neonates younger than 6 hours were randomized to normothermia or 72-hour hypothermia (33.5 °C), and those 6 hours or older and already receiving whole-body hypothermia were randomized to rewarming after 48 or 72 hours of hypothermia. Main Outcomes and Measures: Thalamic N-acetyl aspartate (NAA) concentration (mmol/kg wet weight), assessed by cerebral MR imaging and thalamic spectroscopy between 4 and 7 days after birth using harmonized sequences. Results: Of 225 eligible neonates, 101 were recruited (54 males [53.5%]); 48 (47.5%) were younger than 6 hours and 53 (52.5%) were 6 hours or older at randomization. Mean (SD) gestational age and birth weight were 39.5 (1.1) weeks and 3378 (380) grams in the normothermia group (n = 34), 38.7 (0.5) weeks and 3017 (338) grams in the 48-hour hypothermia group (n = 31), and 39.0 (1.1) weeks and 3293 (252) grams in the 72-hour hypothermia group (n = 36). More neonates in the 48-hour (14 of 31 [45.2%]) and 72-hour (13 of 36 [36.1%]) groups required intubation at birth than in the normothermic group (3 of 34 [8.8%]). Ninety-nine neonates (98.0%) had MR imaging data and 87 (86.1%), NAA data. Injury scores on conventional MR biomarkers were similar across groups. The mean (SD) NAA level in the normothermia group was 10.98 (0.92) mmol/kg wet weight vs 8.36 (1.23) mmol/kg wet weight (mean difference [MD], -2.62 [95% CI, -3.34 to -1.89] mmol/kg wet weight) in the 48-hour and 9.02 (1.79) mmol/kg wet weight (MD, -1.96 [95% CI, -2.66 to -1.26] mmol/kg wet weight) in the 72-hour hypothermia group. Seizures occurred beyond 6 hours after birth in 4 neonates: 1 (2.9%) in the normothermia group, 1 (3.2%) in the 48-hour hypothermia group, and 2 (5.6%) in the 72-hour hypothermia group. Conclusions and Relevance: In this pilot RCT, whole-body hypothermia did not improve cerebral MR biomarkers after mild HIE, although neonates in the hypothermia groups were sicker at baseline. Safety and efficacy of whole-body hypothermia should be evaluated in RCTs. Trial Registration: ClinicalTrials.gov Identifier: NCT03409770.

Hypoglycaemia and hyperglycaemia in neonatal encephalopathy: a systematic review and meta-analysis.

IMPORTANCE: Although hypoglycaemia and hyperglycaemia represent the most common metabolic problem in neonates, there is still uncertainty regarding the effects of glucose homoeostasis on the neurological outcomes of infants with neonatal encephalopathy (NE). OBJECTIVE: To systematically investigate the association between neonatal hypoglycaemia and hyperglycaemia with adverse outcome in children who suffered from NE. STUDY SELECTION: We searched Pubmed, Embase and Web of Science databases to identify studies which reported prespecified outcomes and compared infants with NE who had been exposed to neonatal hypoglycaemia or hyperglycaemia with infants not exposed. DATA ANALYSIS: We assessed the risk of bias (ROBINS-I), quality of evidence (Grading of Recommendations, Assessment, Development and Evaluation (GRADE)) for each of the studies. RevMan was used for meta-analysis (inverse variance, fixed effects). MAIN OUTCOME: Death or neurodevelopmental outcomes at 18 months of age or later. RESULTS: 82 studies were screened, 28 reviewed in full and 12 included. Children who were exposed to neonatal hypoglycaemia had higher odds of neurodevelopmental impairment or death (6 studies, 685 infants; 40.6% vs 25.4%; OR=2.17, 95% CI 1.46 to 3.25; p=0.0001). Neonatal exposure to hyperglycaemia was associated with death or neurodisability at 18 months or later (7 studies, 807 infants; 46.1% vs 28.0%; OR=3.07, 95% CI 2.17 to 4.35; p<0.00001). These findings were confirmed in the subgroup analysis, which included only the infants who underwent therapeutic hypothermia. CONCLUSIONS: These data suggest that neonatal hypoglycaemia and hyperglycaemia may be associated with the neurodevelopmental outcome later on in infants with NE. Further studies with long-term follow-up are needed to optimise the metabolic management of these high-risk infants. PROSPERO REGISTRATION NUMBER: CRD42022368870.

Magnetic Resonance Biomarkers and Neurological Outcome of Infants with Mild Hypoxic-Ischaemic Encephalopathy Who Progress to Moderate Hypoxic-Ischaemic Encephalopathy.

BACKGROUND: There is increasing concern that infants with mild hypoxic-ischaemic encephalopathy (HIE) may develop seizures and progress to moderate HIE beyond the therapeutic window for cooling. OBJECTIVE: The aim of this study was to examine the effect of therapeutic hypothermia on magnetic resonance imaging (MRI) biomarkers and neurological outcomes in infants with mild HIE and seizures within 24 h after birth. METHODS: This study shows an observational cohort study on 366 (near)-term infants with mild HIE and normal amplitude-integrated electroencephalography background. RESULTS: Forty-one infants showed progression (11.2%); 29/41 (70.7%) were cooled. Infants with progression showed cerebral metabolite perturbations and higher white matter injury scores compared to those without in both cooled and non-cooled groups (p = 0.001, p = 0.02). Abnormal outcomes were seen in 5/12 (42%) non-cooled and 7/29 (24%) cooled infants with progression (p = 0.26). CONCLUSIONS: Early biomarkers are needed to identify infants with mild HIE at risk of progression. Mild HIE infants with progression showed a higher incidence of brain injury and abnormal outcomes.

Gut microbiota and COVID-19: An intriguing pediatric perspective.

Gastrointestinal (GI) involvement has been reported in approximately 50% of patients with coronavirus disease 2019 (COVID-19), which is due to the pathogenic role of inflammation and the intestinal function of the angiotensin-converting enzyme 2 and its receptor. Accumulating adult data has pointed out that gut dysbiosis might occur in these patients with a potential impact on the severity of the disease, however the role of gut microbiota in susceptibility and severity of COVID-19 disease in children is still poorly known. During the last decades, the crosstalk between gut and lung has been largely recognized resulting in the concept of "gut-lung axis" as a central player in modulating the development of several diseases. Both organs are involved in the common mucosal immune system (including bronchus-associated and gut-associated lymphoid tissues) and their homeostasis is crucial for human health. In this framework, it has been found that the role of GI dysbiosis is affecting the homeostasis of the gut-liver axis. Of note, a gut microbiome imbalance has been linked to COVID-19 severity in adult subjects, but it remains to be clarified. Based on the increased risk of inflammatory diseases in children with COVID-19, the potential correlation between gut microbiota dysfunction and COVID-19 needs to be studied in this population. We aimed to summarize the most recent evidence on this striking aspect of COVID-19 in childhood.

Impact of intrauterine growth restriction on cerebral and renal oxygenation and perfusion during the first 3 days after birth.

Intrauterine growth restriction (IUGR) is associated with a higher incidence of perinatal complications as well as cardiovascular and renal diseases later on. A better insight into the disease mechanisms underlying these sequalae is important in order to identify which IUGR infants are at a higher risk and find strategies to improve their outcome. In this prospective case-control study we examined whether IUGR had any effect on renal and cerebral perfusion and oxygen saturation in term neonates. We integrated near-infrared spectroscopy (NIRS), echocardiographic, Doppler and renal function data of 105 IUGR infants and 105 age/gender-matched controls. Cerebral and renal regional oxygen saturation values were measured by NIRS during the first 12 h after birth. Echocardiography alongside Doppler assessment of renal and anterior cerebral arteries were performed at 6, 24, 48 and 72 h of age. Glomerular and tubular functions were also assessed. We found a left ventricular dysfunction together with a higher cerebral oxygen saturation and perfusion values in the IUGR group. IUGR term infants showed a higher renal oxygen saturation and a reduced oxygen extraction together with a subclinical renal damage, as indicated by higher values of urinary neutrophil gelatinase-associated lipocalin and microalbumin. These data suggest that some of the haemodynamic changes present in growth-restricted foetuses may persist postnatally. The increased cerebral oxygenation may suggest an impaired transition to normal autoregulation as a consequence of intra-uterine chronic hypoxia. The higher renal oxygenation may reflect a reduced renal oxygen consumption due to a subclinical kidney damage.