Whole-body hypothermia in mild neonatal encephalopathy: protocol for a multicentre phase III randomised controlled trial.

BACKGROUND: Mild hypoxic ischemic encephalopathy is associated with sub optimal cognition and learning difficulties at school age. Although whole-body hypothermia reduces death and disability after moderate or severe encephalopathy in high-income countries, the safety and efficacy of hypothermia in mild encephalopathy is not known. The cooling in mild encephalopathy (COMET) trial will examine if whole-body hypothermia improves cognitive development of neonates with mild encephalopathy. METHODS: The COMET trial is a phase III multicentre open label two-arm randomised controlled trial with masked outcome assessments. A total of 426 neonates with mild encephalopathy will be recruited from 50 to 60 NHS hospitals over 2 ½ years following parental consent. The neonates will be randomised to 72 h of whole-body hypothermia (33.5 ± 0.5 C) or normothermia (37.0 ± 0.5 C) within six hours or age. Prior to the recruitment front line clinical staff will be trained and certified on expanded modified Sarnat staging for encephalopathy. The neurological assessment of all screened and recruited cases will be video recorded and centrally assessed for quality assurance. If recruitment occurs at a non-cooling centre, neonates in both arms will be transferred to a cooling centre for continued care, after randomisation. All neonates will have continuous amplitude integrated electroencephalography (aEEG) at least for the first 48 h to monitor for seizures. Predefined safety outcomes will be documented, and data collected to assess resource utilization of health care. A central team masked to trial group allocation will assess neurodevelopmental outcomes at 2 years of age. The primary outcome is mean difference in composite cognitive scores on Bayley scales of Infant and Toddler development 4th Edition. DISCUSSION: The COMET trial will establish the safety and efficacy of whole-body hypothermia for mild hypoxic ischaemic encephalopathy and inform national and international guidelines in high income countries. It will also provide an economic assessment of whole-body hypothermia therapy for mild encephalopathy in the NHS on cost-effectiveness grounds. TRIAL REGISTRATION NUMBER: NCT05889507 June 5, 2023.

Pertussis outbreak in neonates and young infants across Italy, January to May 2024: implications for vaccination strategies.

Since January 2024, Italy experiences a pertussis outbreak, primarily affecting neonates and unvaccinated infants at high risk of severe complications and mortality; 11 major paediatric centres noted 108 hospitalisations and three deaths by 10 May. The outbreak reflects increased circulation of Bordetella pertussis and non-adherence to immunisation recommendations during pregnancy. Public health interventions, including maternal immunisation, vaccination of infants as early as possible and post-exposure prophylaxis, are critical for reducing the burden of pertussis and preventing further mortality.

Heart rate cut-offs to identify non-febrile children with dehydration and acute kidney injury.

We hypothesized that the heart rate (HR) variation in an acute setting compared with HR in wellbeing status could be a good marker of both dehydration and acute kidney injury (AKI). Since HR in wellbeing status is unknown in most cases, we assumed as reliable surrogate the 50th percentile of HR according to age and gender. We evaluated if the estimated percentage of heart rate variation in acute setting compared with 50th percentile of HR (EHRV) could be marker of dehydration and AKI in children. Two independent cohorts, one prospective comprehending 185 children at type 1 diabetes mellitus onset (derivation) and one retrospective comprehending 151 children with acute gastroenteritis and pneumonia (validation), were used to develop and externally validate EHRV as predictor of the ≥ 5% dehydration and/or AKI composite outcome. Febrile patients were excluded. EHRV was calculated as ((HR at admission-50th percentile of HR)/HR at admission) × 100. The prevalences of ≥ 5% dehydration and AKI were 61.1% and 43.8% in the derivation and 34.4% and 24.5% in the validation cohort. For the ≥ 5% dehydration and/or AKI composite outcome, the area under receiver-operating characteristic curve of the EHRV in the derivation cohort was 0.69 (95%CI, 0.62-0.77; p < 0.001) and the best EHRV cut-off was > 24.5%. In the validation cohort, EHRV > 24.5% showed specificity = 100% (95%CI, 96.2-100.0), positive predictive value = 100%, and negative predictive value = 67.1% (95%CI, 64.7-69.5). The positive likelihood ratio was infinity, and odds ratio was not calculable because all the patients with EHRV > 24.5% showed ≥ 5% dehydration and/or AKI.    Conclusions: EHRV appears a rather reliable marker of dehydration and AKI. Further validations could allow implementing EHRV in the clinical practice. What is Known: • Increased heart rate (HR) is an easily and quickly detectable sign of dehydration in childhood, but its cut-off to suspect dehydration or acute kidney injury (AKI) is not defined. What is New: • We found that a percentage of estimated HR variation in acute setting in comparison with 50th percentile of HR (EHRV)>24.5% predicted ≥5% dehydration and/or AKI in non-febrile patients. • We provide a one-page tool to suspect ≥5% dehydration and/or AKI on the basis of the HR. If furtherly validated, this tool could be implemented in the daily clinical practice.

Effect of intra-partum Oxytocin on neonatal encephalopathy: a systematic review and meta-analysis.

BACKGROUND: Oxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy. METHODS: The protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (≥36 weeks' gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals. RESULTS: We included data from seven studies (6 Case-control studies, 1 cluster-randomised trial) of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36 weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; p < 0.00001). CONCLUSIONS: Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.

Continuous glucose monitoring profile during therapeutic hypothermia in encephalopathic infants with unfavorable outcome.

BACKGROUND: The relation between glucose homeostasis and outcome in hypoxic-ischemic encephalopathy (HIE) is unclear. To investigate whether glucose abnormalities assessed by using continuous interstitial glucose monitoring (CGM) correlate with later neurological outcomes in HIE. METHODS: Prospective cohort study recruiting full-term neonates who received therapeutic hypothermia for HIE. CGM devices were placed soon after birth and recorded glucose profile for 3 days. The association between hypoglycemia (≤50 mg/dL), hyperglycemia (>144 mg/dL) and primary outcome defined as death or moderate or severe disability was examined with generalized estimating equations adjusted for Apgar scores, umbilical artery pH and base deficit. Neurodevelopmental outcome was assessed between 18 and 24 months. RESULTS: Fifty-four neonates had outcome data available for the analysis; 19 of them (35%) had adverse outcome. Longer duration of hypoglycemia (OR 7.1, 95% CI 1.8-20.3, P < 0.001) and hyperglycemia (OR 5.4, 95% CI 1.6-15.7, P < 0.001), a greater area under the hypoglycemic (OR 2.6, 95% CI 1.4-4.6, P = 0.04) and hyperglycemic (OR 6.4, 95% CI 1.9-16.3, P < 0.001) curve were significantly associated with adverse outcomes. CONCLUSION: Both hyper and hypoglycemia may be associated with adverse outcome in neonates with HIE. Future studies are needed to assess their prognostic association with neurological outcome. IMPACT: Glucose abnormalities during therapeutic hypothermia are associated with later neurological outcomes.Increased glucose variability correlates to the neurological outcome between 18 and 24 months.This study provides the first data on the continuous glucose profile in a group of HIE infants followed up to 2 years of age.Glucose homeostasis represents a key point in the management of HIE patients.Further research is needed to find the appropriate glycemic target in this population.

Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months.

BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

Presepsin for the detection of early-onset sepsis in preterm newborns.

BACKGROUND: Early-onset sepsis (EOS) is responsible for an important fraction of neonatal morbidity and mortality all over the world. The aim of this study was to assess whether presepsin (P-SEP) can be a more accurate biomarker of EOS compared with pro-calcitonin (PCT) and C-reactive protein (CRP). STUDY DESIGN: Consecutive preterm neonates (<34 wk gestational age, admitted to Neonatal Intensive Care Unit by 6 h of age and undergoing sepsis evaluation) were recruited as part of a case-matched control study. We determined CRP, PCT and P-SEP at admission, and then at 12, 24, and 48 h of age. Neonates recruited into the study were divided into the EOS group (n = 32) and the uninfected group (n =38) according to their infection screening. RESULTS: P-SEP values were significantly higher in the EOS group than in the uninfected group at different time intervals. The highest accuracy was achieved by P-SEP at 24 h after birth. The AUC for P-SEP was 0.97. In our sample, P-SEP achieved the best accuracy for prediction of EOS at the cut-off of 788 ng/l with 93% sensitivity and 100% specificity. CONCLUSIONS: This study shows that P-SEP is significantly higher in preterm infants with EOS compared with uninfected infants.

Small renal size in newborns with spina bifida: possible causes.

BACKGROUND: Previous studies reported that children with neural tube defects, but without any history of intrinsic renal diseases, have small kidneys when compared with age-matched standard renal growth. The aim of this study was to investigate the possible causes of small renal size in children with spina bifida by comparing growth hormone deficiency, physical limitations and hyperhomocysteinemia. METHODS: The sample included 187 newborns with spina bifida. Renal sizes in the patients were assessed by using maximum measurement of renal length and the measurements were compared by using the Sutherland monogram. According to the results, the sample was divided into two groups--a group of 120 patients with small kidneys (under the third percentile) and a control group of 67 newborns with normal kidney size. Plasma total homocysteine was investigated in mothers and in their children. Serum insulin-like growth factor-1 (IGF-1) levels were measured. RESULTS: Serum IGF-1 levels were normal in both groups. Children and mothers with homocysteine levels >10 µmol/l were more than twice as likely to have small kidneys and to give to birth children with small kidneys, respectively, compared with newborns and mothers with homocysteine levels <10 µmol/l. An inverse correlation was also found between the homocysteine levels of mothers and kidney sizes of children (r = - 0.6109 P ≤ 0.01). CONCLUSIONS: It is highly important for mothers with hyperhomocysteinemia to be educated about benefits of folate supplementation in order to reduce the risk of small renal size and lower renal function in children.

Editorial on the Special Issue "Advances in Pediatric Acute Kidney Injury".

Acute kidney injury (AKI) refers to a swift decline in kidney function, marked by the reduced excretion of waste products and disturbances in fluid and electrolyte balance [...].

Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India.

Background: Although levetiracetam and phenytoin are widely used antiseizure medications (ASM) in neonates, their efficacy on seizure freedom is unclear. We evaluated electroencephalographic (EEG) seizure freedom following sequential levetiracetam and phenytoin in neonatal seizures unresponsive to phenobarbital. Methods: We recruited neonates born ≥35 weeks and aged <72 h who had continued electrographic seizures despite phenobarbital, from three Indian hospitals, between 20 June 2020 and 31 July 2022. The neonates were treated with intravenous levetiracetam (20 mg/kg x 2 doses, second line) followed by phenytoin (20 mg/kg x 2 doses, third line) if seizures persisted. The primary outcome was complete seizure freedom, defined as an absence of seizures on EEG for at least 60 min within 40 min from the start of infusion. Findings: Of the 206 neonates with continued seizures despite phenobarbital, 152 received levetiracetam with EEG. Of these one EEG was missing, 47 (31.1%) were in status epilepticus, and primary outcome data were available in 145. Seizure freedom occurred in 20 (13.8%; 95% CI 8.6%-20.5%) after levetiracetam; 16 (80.0%) responded to the first dose and 4 (20.0%) to the second dose. Of the 125 neonates with persisting seizures after levetiracetam, 114 received phenytoin under EEG monitoring. Of these, the primary outcome data were available in 104. Seizure freedom occurred in 59 (56.7%; 95% CI 46.7%-66.4%) neonates; 54 (91.5%) responded to the first dose and 5 (8.5%) to the second dose. Interpretation: With the conventional doses, levetiracetam was associated with immediate EEG seizure cessation in only 14% of phenobarbital unresponsive neonatal seizures. Additional treatment with phenytoin along with levetiracetam attained seizure freedom in further 57%. Safety and efficacy of higher doses of levetiracetam should be evaluated in well-designed randomised controlled trials. Funding: National Institute for Health and Care Research (NIHR) Research and Innovation for Global Health Transformation (NIHR200144).

Whole-Blood Gene Expression Profile After Hypoxic-Ischemic Encephalopathy.

Importance: Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden. Objective: To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia. Design, Setting, and Participants: This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023. Exposure: Whole-blood RNA that underwent next-generation sequencing. Main Outcome and Measures: The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort. Results: The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and gestational age of 39.2 (38.9-40.4) weeks. A total of 1793 significant genes in the HIC cohort and 99 significant genes in the South Asia cohort were associated with adverse outcome (false discovery rate <0.05). Only 11 of these genes were in common, and all had opposite direction in fold change. The most significant pathways associated with adverse outcome were downregulation of eukaryotic translation initiation factor 2 signaling in the HIC cohort (z score = -4.56; P < .001) and aldosterone signaling in epithelial cells in the South Asia cohort (z score = null; P < .001). The genome expression profile of neonates with HIE (n = 35) at birth, 24 hours, 48 hours, and 72 hours remained significantly different from that of age-matched healthy controls in the HIC cohort (n = 14). Conclusions and Relevance: This case-control study found that disease mechanisms underlying HIE were primarily associated with acute hypoxia in the HIC cohort and nonacute hypoxia in the South Asia cohort. This finding might explain the lack of hypothermic neuroprotection.

Duration of birth depression and neurodevelopmental outcomes after whole-body hypothermia for hypoxic ischemic encephalopathy in India, Sri Lanka and Bangladesh - an exploratory analysis of the HELIX trial.

Background: Effect of duration of birth depression on neurodevelopmental outcomes in low- and middle-income countries (LMICs) is not known. We examined the association of birth depression with brain injury, neurodevelopmental outcomes, and hypothermia after hypoxic ischemic encephalopathy (HIE) in south Asia. Methods: We compared cerebral magnetic resonance (MR) at 2 weeks, and adverse outcomes (death or moderate or severe disability) at 18 months in 408 babies with moderate or severe HIE who had long birth depression (positive pressure ventilation (PPV) >10 min or Apgar score<6 at 10 min or cord pH < 7.0) and short birth depression (PPV for 5-10 min or Apgar score<6 at 5 min, but ≥6 at 10 min). Findings: Long depression group (n = 201) had more severe HIE (32.8% versus 6.8%), mortality (47.5% versus 26.4%), death or disability at 18 months (62.2% versus 35.4%) (all p < 0.001), MR injury (Odds ratio; 95% CI) to basal ganglia (2.4 (1.3, 4.1); p = 0.003), posterior limb of internal capsule (2.3 (1.3, 4.3); p < 0.001) and white matter (1.7 (1.1, 2.7); p = 0.021), and lower thalamic N-acetylaspartate levels (7.69 ± 1.84 versus 8.29 ± 1.60); p = 0.031) than short depression group (n = 207). Three babies had no heartbeat at 5 min, of which 1 died and 2 survived with severe disability. No significant interaction between the duration of birth depression and whole-body hypothermia was seen for any of the MR biomarker or clinical outcomes. Interpretation: Long birth depression was associated with more brain injury and adverse outcomes than short depression. Effect of hypothermia was not modified by duration of birth depression. Funding: National Institute for Health Research.

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.