Skin-to-skin transfer from the delivery room to the neonatal unit for neonates of 1,500g or above: a feasibility and safety study.

Objective: Immediate skin-to-skin contact (SSC) is already standard care for healthy term newborns, but its use for term or preterm newborns requiring admission to neonatal intensive care unit (NICU) with or without respiratory support is challenging. This study aimed to assess the safety and feasibility of SSC during the transfer of newborn infants, using a new purpose-built mobile shuttle care-station, called "Tandem". Material and methods: A monocentric prospective observational study was conducted at the tertiary referral center of the Université libre de Bruxelles in Brussels, Belgium after ethical approval by Hopital Erasme's Ethics Committee (ClinicalTrials.gov ID: NCT06198478). Infants born with a birth weight above 1,500 g were included. Following initial stabilization, infants were placed in SSC with one of their parents and transferred to the NICU using the Tandem. Results: Out of 65 infants initially included, 64 (98.5%) were successfully transported via SSC using the Tandem. One transfer was not successful due to last minute parental consent withdrawal. The median (range) duration of continuous skin-to-skin contact after birth was 120 min (10-360). SSC transfers were associated with gradually decreasing heart rate (HR) values, stable oxygen saturation levels (SpO2), and no increase in median fraction of inspired oxygen (FiO2). Heatloss was predominantly observed during initial setup of SSC. There was no significant difference in the occurrence of tachycardia, desaturation or hypothermia between preterm and term neonates. No equipment failures compromising the transfer were recorded. Conclusion: Skin-to-skin transfer of infants with a birthweight of equal or above 1,500 g using the Tandem shuttle is feasible and associated with stable physiological parameters. This method facilitates early bonding and satisfies parents. Clinical Trial Registration: ClinicalTrials.gov (NCT06198478).

A novel homozygous variant in SLC25A46 gene associated with pontocerebellar hypoplasia type 1E: a case report.

Neonatal encephalopathy (NE) is a complex clinical condition with diverse etiologies. Hypoxic-ischemic encephalopathy (HIE) is a major contributor to NE cases. However, distinguishing NE subtypes, such as pontocerebellar hypoplasia type 1E (PCH1E), from HIE can be challenging due to overlapping clinical features. Here, we present a case of PCH1E in a neonate with a homozygous mutation c.72delT p. (Phe24LeufsTer20) in the SLC25A46 gene. The severity of PCH1E associated NE highlighted the significance of early recognition to guide appropriate clinical management.

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

Case Report: Neonatal Unexplained HUS Treated With Complement Inhibitor Eculizumab.

Background: Hemolytic uremic syndrome (HUS) is rare in neonates. It is probably an under-recognized condition in the early postnatal period as it presents similarly to the most common perinatal asphyxia and to differentiate the two conditions is challenging. We describe the clinical presentation of a potential new subtype of neonatal HUS triggered by hypoxic-ischemic event. Our patient was successfully treated by a single dose of Eculizumab as early as at 9 days of life. Case Report: A 35-weeks infant was born with low hemoglobin and subsequently developed respiratory distress, hypotension, and acidosis. Blood transfusion was administered, acidosis corrected, neurological examination remained reassuring. Few hours later he developed renal failure, macroscopic hematuria, hemobilia, thrombocytopenia and coagulopathy refractory to platelet and fresh frozen plasma transfusions. No infection was found. Haptoglobin was non-measurable, and schistocytes present, complement factors C3, C4 and B were low, FBb increased. HUS was suspected. A single dose of Eculizumab™ was administered on day 9 of life. No genetic mutation of atypical HUS was found. He was discharged with improving renal function and developing cholestasis. Conclusion: In neonates with hemolytic anemia, thrombocytopenia, hematuria and renal failure, HUS should be suspected. In neonatal HUS Eculizumab should be considered as first-line therapy and discontinuation can be considered if no genetic mutation is found and clinical condition improves. In very young patients, cholestasis could appear as potential side effect of Eculizumab™.

Serum copeptin and neuron specific enolase are markers of neonatal distress and long-term neurodevelopmental outcome.

The objective of this study was to evaluate the early changes in serial serum levels of copeptin and neuron-specific enolase (NSE) in neonates diagnosed with birth asphyxia, and to determine whether these biomarkers measured in the first 168 hours after birth are predictive of long-term neurodevelopmental outcome. Copeptin and NSE levels were measured from serum samples collected 6, 12, 24, 48, 72, and 168 hours after birth from 75 term neonates diagnosed with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia for 72 hours. In addition, serum copeptin levels after birth were measured from 10 HIE diagnosed neonates, who were randomized to the normothermic arm of the TOBY cohort. All neonates underwent neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development-II at two years of age. Copeptin levels were highest at 6 hours after birth and steadily decreased, whereas the highest NSE levels were measured at 24 hours after birth. The biomarker levels correlated with blood-gas parameters (base excess, pH and lactate) at 6 and 12 hours after birth. Copeptin and NSE levels in the early postnatal period were significantly higher in neonates with poor outcome compared to those with favorable outcome at two years of age. Furthermore, in the TOBY cohort, copeptin levels were significantly lower in hypothermic compared to normothermic neonates. To conclude, copeptin and NSE measured in the early postnatal period are potential prognostic biomarkers of long-term neurodevelopmental outcome in term neonates diagnosed with HIE and treated with therapeutic hypothermia.

Systemic pro-inflammatory cytokine status following therapeutic hypothermia in a piglet hypoxia-ischemia model.

BACKGROUND: Inflammatory cytokines are implicated in the pathogenesis of perinatal hypoxia-ischemia (HI). The influence of hypothermia (HT) on cytokines after HI is unclear. Our aim was to assess in a piglet asphyxia model, under normothermic (NT) and HT conditions: (i) the evolution of serum cytokines over 48 h and (ii) cerebrospinal fluid (CSF) cytokine levels at 48 h; (iii) serum pro/anti-inflammatory cytokine profile over 48 h and (iv) relation between brain injury measured by magnetic resonance spectroscopy (MRS) and brain TUNEL positive cells with serum cytokines, serum pro/anti-inflammatory cytokines and CSF cytokines. METHODS: Newborn piglets were randomized to NT (n = 5) or HT (n = 6) lasting 2-26 h after HI. Serum samples were obtained 4-6 h before, during and at 6-12 h intervals after HI; CSF was obtained at 48 h. Concentrations of interleukin (IL)-1ß, -4, -6, -8, -10 and TNF-α were measured and pro/anti-inflammatory status compared between groups. White matter and thalamic voxel lactate/N-acetyl aspartate (Lac/NAA) (a measure of both oxidative metabolism and neuronal loss) were acquired at baseline, after HI and at 24 and 36 h. RESULTS: Lac/NAA was reduced at 36 h with HT compared to NT (p = 0.013 basal ganglia and p = 0.033 white matter). HT showed lower serum TNF-α from baseline to 12 h (p < 0.05). Time-matched (acquired within 5 h of each other) serum cytokine and MRS showed correlations between Lac/NAA and serum IL-1ß and IL-10 (all p < 0.01). The pro/anti-inflammatory ratios IL-1ß/IL-10, IL-6/IL-10, IL-4/IL-10 and IL-8/IL-10 were similar in NT and HT groups until 36 h (24 h for IL-6/IL-10); after this, 36 h pro/anti-inflammatory cytokine ratios in the serum were higher in HT compared to NT (p < 0.05), indicating a pro-inflammatory cytokine surge after rewarming in the HT group. In the CSF at 48 h, IL-8 was lower in the HT group (p < 0.05). At 48 h, CSF TNF-α correlated with Lac/NAA (p = 0.02) and CSF IL-8 correlated with white matter TUNEL positive cell death (p = 0.04). CONCLUSIONS: Following cerebral HI, there was a systemic pro-inflammatory surge after rewarming in the HT group, which is counterintuitive to the putative neuroprotective effects of HT. While serum cytokines were variable, elevations in CSF inflammatory cytokines at 48 h were associated with MRS Lac/NAA and white matter cell death.

Brain cell death is reduced with cooling by 3.5°C to 5°C but increased with cooling by 8.5°C in a piglet asphyxia model.

BACKGROUND AND PURPOSE: In infants with moderate to severe neonatal encephalopathy, whole-body cooling at 33°C to 34°C for 72 hours is standard care with a number needed to treat to prevent a adverse outcome of 6 to 7. The precise brain temperature providing optimal neuroprotection is unknown. METHODS: After a quantified global cerebral hypoxic-ischemic insult, 28 piglets aged <24 hours were randomized (each group, n=7) to (1) normothermia (38.5°C throughout) or whole-body cooling 2 to 26 hours after insult to (2) 35°C, (3) 33.5°C, or (4) 30°C. At 48 hours after hypoxia-ischemia, delayed cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and cleaved caspase 3) and microglial ramification (ionized calcium-binding adapter molecule 1) were evaluated. RESULTS: At 48 hours after hypoxia-ischemia, substantial cerebral injury was found in the normothermia and 30°C hypothermia groups. However, with 35°C and 33.5°C cooling, a clear reduction in delayed cell death and microglial activation was observed in most brain regions (P<0.05), with no differences between 35°C and 33.5°C cooling groups. A protective pattern was observed, with U-shaped temperature dependence in delayed cell death in periventricular white matter, caudate nucleus, putamen, hippocampus, and thalamus. A microglial activation pattern was also seen, with inverted U-shaped temperature dependence in periventricular white matter, caudate nucleus, internal capsule, and hippocampus (all P<0.05). CONCLUSIONS: Cooling to 35°C (an absolute drop of 3.5°C as in therapeutic hypothermia protocols) or to 33.5°C provided protection in most brain regions after a cerebral hypoxic-ischemic insult in the newborn piglet. Although the relatively wide therapeutic range of a 3.5°C to 5°C drop in temperature reassured, overcooling (an 8.5°C drop) was clearly detrimental in some brain regions.

Systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia: implications for therapeutic hypothermia.

INTRODUCTION: The precise temperature for optimal neuroprotection in infants with neonatal encephalopathy is unclear. Our aim was to assess systemic effects of whole-body cooling to 35 °C, 33.5 °C, and 30 °C in a piglet model of perinatal asphyxia. METHODS: Twenty-eight anesthetized male piglets aged <24 h underwent hypoxia-ischemia (HI) and were randomized to normothermia or cooling to rectal temperature (Trec) 35 °C, 33.5 °C, or 30 °C during 2-26 h after insult (n = 7 in each group). HR, MABP, and Trec were recorded continuously. RESULTS: Five animals cooled to 30 °C had fatal cardiac arrests. During 30 °C cooling, heart rate (HR) was lower vs. normothermia (P < 0.001). Although mean arterial blood pressure (MABP) did not vary between groups, more fluid boluses were needed at 30 °C than at normothermia (P < 0.02); dopamine use was higher at 30 °C than at normothermia or 35 °C (P = 0.005 and P = 0.02, respectively). Base deficit was increased at 30 °C at 12, 24, and 36 h vs. all other groups (P < 0.05), pH was acidotic at 36 h vs. normothermia (P = 0.04), and blood glucose was higher for the 30 °C group at 12 h vs. the normothermia and 35 °C groups (P < 0.05). Potassium was lower at 12 h in the 30 °C group vs. the 33.5 °C and 35 °C groups. There was no difference in cortisol level between groups. DISCUSSION: Cooling to 30 °C led to metabolic derangement and more cardiac arrests and deaths than cooling to 33.5 °C or 35 °C. Inadvertent overcooling should be avoided.

Serum S100B and neuron-specific enolase levels in normothermic and hypothermic infants after perinatal asphyxia.

AIM: Serum S100B and neuron-specific enolase (NSE) levels are elevated after perinatal asphyxia, but the influence of hypothermia on these proteins has not been previously reported. The aim of this study was to evaluate the effect of systemic hypothermia on these protein levels after perinatal asphyxia, time course, and association with perinatal factors and neurodevelopmental outcome at 2 years of age. METHODS: Serum S100B and NSE levels were measured at fixed time points in asphyxiated infants treated with standard intensive care on hypothermia (HT: n = 13) or normothermia (NT: n = 11). RESULTS: Serum S100B and NSE levels were grossly elevated in both HT and NT groups. Compared with the values at 6 h of age, S100B values decreased over time in both groups (NT: p = 0.002, HT: p = 0.04). Serum S100B values were lower in HT infants compared with those in NT infants (p = 0.047 at 48 h). Serum S100B and NSE values were significantly higher in infants who died or developed severe neurological impairment (S100B, p < 0.05 at all time points; NSE, p = 0.036 at 24 h of age). CONCLUSION: Both NSE and S100B levels are highly elevated following asphyxia. Serum S100B levels were lower in the HT group and strongly correlated with the neurodevelopmental outcome.

Xenon augmented hypothermia reduces early lactate/N-acetylaspartate and cell death in perinatal asphyxia.

OBJECTIVE: Additional treatments for therapeutic hypothermia are required to maximize neuroprotection for perinatal asphyxial encephalopathy. We assessed neuroprotective effects of combining inhaled xenon with therapeutic hypothermia after transient cerebral hypoxia-ischemia in a piglet model of perinatal asphyxia using magnetic resonance spectroscopy (MRS) biomarkers supported by immunohistochemistry. METHODS: Thirty-six newborn piglets were randomized (all groups n = 9), with intervention from 2 to 26 hours, to: (1) normothermia; (2) normothermia + 24 hours 50% inhaled xenon; (3) 24 hours hypothermia (33.5°C); or (4) 24 hours hypothermia (33.5°C) + 24 hours 50% inhaled xenon. Serial MRS was acquired before, during, and up to 48 hours after hypoxia-ischemia. RESULTS: Mean arterial blood pressure was lower in all treatment groups compared with normothermia (p < 0.01) (although >40mmHg); the combined therapy group required more fluid boluses (p < 0.05) and inotropes (p < 0.001). Compared with no intervention, both hypothermia and xenon-augmented hypothermia reduced the temporal regression slope magnitudes for phosphorus-MRS inorganic phosphate/exchangeable phosphate pool (EPP) and phosphocreatine/EPP (both p < 0.05); for lactate/N-acetylaspartate (NAA), only xenon-augmented hypothermia reduced the slope (p < 0.01). Xenon-augmented hypothermia also reduced transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)(+) nuclei and caspase 3 immunoreactive cells in parasagittal cortex and putamen and increased microglial ramification in midtemporal cortex compared with the no treatment group (p < 0.05). Compared with hypothermia, however, combination treatment did not reach statistical significance for any measure. Lactate/NAA showed a strong positive correlation with TUNEL; nucleotide triphosphate/EPP showed a strong negative correlation with microglial ramification (both p < 0.01). INTERPRETATION: Compared with no treatment, xenon-augmented hypothermia reduced cerebral MRS abnormalities and cell death markers in some brain regions. Compared with hypothermia, xenon-augmented hypothermia did not reach statistical significance for any measure. The safety and possible improved efficacy support phase II trials.

Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury.

According to increasing evidence, hypothermia can significantly improve outcomes in term neonates manifesting asphyxic insult and hypoxic-ischemic encephalopathy. Oxidative stress plays a key role in hypoxic-ischemic and inflammatory brain injuries. We investigated the impact of hypothermia on oxidative stress in babies with hypoxic-ischemic encephalopathy. Term infants were randomly selected for treatment with moderate whole body hypothermia or standard care on normothermia, after perinatal asphyxia. Total hydroperoxides as biochemical markers of oxidative stress, and C-reactive protein as a marker of inflammation, were assayed in blood samples drown at 6, 12, 24, 48, and 72 postnatal hours. In both hypothermic and normothermic groups, total hydroperoxides and C-reactive protein exhibited a continuous increase in the first days after birth. Nevertheless, a tendency was evident for slower and smaller elevations of total hydroperoxides and C-reactive protein in hypothermic compared with normothermic infants. A significant correlation was observed between total hydroperoxides and C-reactive protein in all patients, indicating an association between inflammation and oxidative stress during asphyxia. The slower increase and lower peaks of total hydroperoxides in the hypothermic group support the hypothesis that postasphyxic oxidative stress may be reduced by hypothermia.

Experimental treatments for hypoxic ischaemic encephalopathy.

Hypoxic ischaemic encephalopathy continues to be a significant cause of death and disability worldwide. In the last 1-2 years, therapeutic hypothermia has entered clinical practice in industrialized countries and neuroprotection of the newborn has become a reality. The benefits and safety of cooling under intensive care settings have been shown consistently in trials; therapeutic hypothermia reduces death and neurological impairment at 18 months with a number needed to treat of approximately nine. Unfortunately, around half the infants who receive therapeutic hypothermia still have abnormal outcomes. Recent experimental data suggest that the addition of another agent to cooling may enhance overall protection either additively or synergistically. This review discusses agents such as inhaled xenon, N-acetylcysteine, melatonin, erythropoietin and anticonvulsants. The role of biomarkers to speed up clinical translation is discussed, in particular, the use of the cerebral magnetic resonance spectroscopy lactate/N-acetyl aspartate peak area ratios to provide early prognostic information. Finally, potential future therapies such as regeneration/repair and postconditioning are discussed.