Increase of Parkin and ATG5 plasmatic levels following perinatal hypoxic-ischemic encephalopathy.

Brain injury at birth is an important cause of neurological and behavioral disorders. Hypoxic-ischemic encephalopathy (HIE) is a critical cerebral event occurring acutely or chronically at birth with high mortality and morbidity in newborns. Therapeutic strategies for the prevention of brain damage are still unknown, and the only medical intervention for newborns with moderate-to-severe HIE is therapeutic hypothermia (TH). Although the neurological outcome depends on the severity of the initial insult, emerging evidence suggests that infants with mild HIE who are not treated with TH have an increased risk for neurodevelopmental impairment; in the current clinical setting, there are no specific or validated biomarkers that can be used to both correlate the severity of the hypoxic insult at birth and monitor the trend in the insult over time. The aim of this work was to examine the presence of autophagic and mitophagic proteins in bodily fluids, to increase knowledge of what, early at birth, can inform therapeutic strategies in the first hours of life. This is a prospective multicentric study carried out from April 2019 to April 2020 in eight third-level neonatal intensive care units. All participants have been subjected to the plasma levels quantification of both Parkin (a protein involved in mitophagy) and ATG5 (involved in autophagy). These findings show that Parkin and ATG5 levels are related to hypoxic-ischemic insult and are reliable also at birth. These observations suggest a great potential diagnostic value for Parkin evaluation in the first 6 h of life.

Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial.

BACKGROUND: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). METHODS: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. FINDINGS: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57-0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7-135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). INTERPRETATION: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. FUNDING: None.

Role of bilevel positive airway pressure in the management of preterm newborns who have received surfactant.

AIM: Surfactant given during brief intubation followed by immediate extubation on nasal continuous positive airway pressure [Intubation-Surfactant-Extubation (InSurE) approach] is used to treat respiratory distress syndrome in newborns. Our aim was to evaluate whether bilevel positive airway pressure (BiPAP) after InSurE failure is able to prevent the need for mechanical ventilation (MV). METHODS: Chart data of infants with a birth weight <1500 gr or GA <32weeks undergoing InSurE in the period 2002-2008 in an Italian Tertiary Neonatal Intensive Care Unit were reviewed retrospectively. InSurE failure was defined as follows: FiO(2) >0.4, respiratory acidosis or intractable apnoea within 1 week. After InSurE failure, newborns born before the implementation of BiPAP (historical control group) received MV, whereas those born after BiPAP implementation (BiPAP group) received BiPAP and underwent MV only if failure criteria persisted. The two groups were compared to evaluate whether BiPAP reduced the need for MV in the 7 days after InSurE failure. RESULTS: Six of twenty-two (27%) and 14 of the 38 (37%) infants failed InSurE in the two groups, respectively (p > 0.05). Need for MV was 27% in the historical control group versus 0% in the BiPAP group (risk estimate, 3.38; 95% CI, 2.24, 5.09; p = 0.001). CONCLUSIONS: BiPAP reduced the need for MV after InSurE failure.

Seizure burden and neurodevelopmental outcome in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia: A single center observational study.

OBJECTIVE: To examine the relationship between electrographic seizures and developmental outcome at 18 and 24 months in neonates with moderate and severe hypoxic-ischemic encephalopathy [HIE] treated with therapeutic hypothermia [TH]. STUDY DESIGN: 30 term infants with moderate-severe HIE treated with TH were enrolled prospectively from June 2012 to May 2018. All had continuous single channel amplitude integrated EEG (aEEG) monitoring for a minimum of 72 h and brain MR within 4 weeks. The aEEG was classified by severity of background and seizure burden. MR images were graded by the severity of injury. Outcome (defined abnormal in case of death, dyskinetic or spastic quadriplegic cerebral palsy, epilepsy, or Bayley III score < 85 in all three subscales or < 70 in any individual subscale) was assessed at 18 and 24 months. RESULTS: Seizures were recorded in 24 out of 30 [80 %] neonates and an abnormal outcome was observed in 7 [23 %] of infants. Patients with poor outcome had a statistically significant correlation with: high seizure burden (p = 0.0004), need for more than one antiepileptic drugs (p = 0.006), a persistent abnormal aEEG trace at 48 h (p = 0.0001) and moderate-severe brain injury at MRI (p = 0.0001). Moreover, infants with status epilepticus or frequent seizures reported a significantly association with abnormal MR imaging and poor outcome than patients with sporadic seizures (p = 0.0009). CONCLUSION: The role of seizures in the pathogenesis of brain injury remains controversial. In our cohort the presence of seizures, per se, was not associated with abnormal outcome; however a high seizure burden as well as a persistent abnormal aEEG background pattern and MR lesions resulted significantly associated with poor prognosis.

Severe neurologic and hepatic toxicity in a newborn prenatally exposed to methamphetamine. A case report.

OBJECTIVE: In the recent years the increase of methamphetamines (MTA) abusers women has become an emerging problem. Very little data has been published regarding the effects of prenatal MTA exposure. We describe a case of MTA related toxicity in a term newborn which have early onset of neonatal encephalopathy and liver failure. CASE REPORT: A term infant born to a MTA abuser mother developed seizures and severe neurological symptoms shortly after birth. Methamphetamine was detected both in maternal and in neonatal urine. The laboratoristic tests revealed severe hepatic insufficiency, coagulopathy and thrombocytopenia. Due to neonatal encephalopathy the newborn underwent hypothermia. Phenobarbital, fresh frozen plasma, platelet transfusions and vitamin K were administered. Cranial ultrasonography and magnetic resonance imaging (MRI) showed diffuse white matter damage and two ischemic-hemorrhagic cerebral lesions. Gradually the clinical conditions improved, at 1 month MRI showed a stabilization of cerebral lesions with residual diffuse leukomalacia. Physiotherapy and neurological follow up is ongoing to evaluate the long term effects. CONCLUSIONS: although infrequent, MTA-related toxicity should be suspected in infants with neurologic and hepatic symptoms. Further studies are warranted to confirm our findings in order to identify newborns at high risk of acute MTA toxicity in time to provide them the appropriate support.

Early predictors of short term neurodevelopmental outcome in asphyxiated cooled infants. A combined brain amplitude integrated electroencephalography and near infrared spectroscopy study.

BACKGROUND: Brain Cooling (BC) represents the elective treatment in asphyxiated newborns. Amplitude Integrated Electroencephalography (aEEG) and Near Infrared Spectroscopy (NIRS) monitoring may help to evaluate changes in cerebral electrical activity and cerebral hemodynamics during hypothermia. OBJECTIVES: To evaluate the prognostic value of aEEG time course and NIRS data in asphyxiated cooled infants. METHODS: Twelve term neonates admitted to our NICU with moderate-severe Hypoxic-Ischemic Encephalopathy (HIE) underwent selective BC. aEEG and NIRS monitoring were started as soon as possible and maintained during the whole hypothermic treatment. Follow-up was scheduled at regular intervals; adverse outcome was defined as death, cerebral palsy (CP) or global quotient <88.7 at Griffiths' Scale. RESULTS: 2/12 Infants died, 2 developed CP, 1 was normal at 6 months of age and then lost at follow-up and 7 showed a normal outcome at least at 1 year of age. The aEEG background pattern at 24 h of life was abnormal in 10 newborns; only 4 of them developed an adverse outcome, whereas the 2 infants with a normal aEEG developed normally. In infants with adverse outcome NIRS showed a higher Tissue Oxygenation Index (TOI) than those with normal outcome (80.0±10.5% vs 66.9±7.0%, p=0.057; 79.7±9.4% vs 67.1±7.9%, p=0.034; 80.2±8.8% vs 71.6±5.9%, p=0.069 at 6, 12 and 24 h of life, respectively). CONCLUSIONS: The aEEG background pattern at 24h of life loses its positive predictive value after BC implementation; TOI could be useful to predict early on infants that may benefit from other innovative therapies.

Effect of posture on brain hemodynamics in preterm newborns not mechanically ventilated.

BACKGROUND: Changes in head posture influence brain hemodynamics. Optimal positioning has been recommended as 1 of 10 potentially better practices to reduce the incidence of brain injury in preterm newborns. OBJECTIVES: The aim of this study was to evaluate by near-infrared spectroscopy (NIRS) the effect of different head and body positions and the influence of gestational age (GA) and nasal continuous positive airway pressure on brain hemodynamics in very preterm newborns. METHODS: 24 stable preterm newborns were studied by NIRS in 6 different postures including head rotation and head inclination in both supine and prone positions. Changes in normalized tissue hemoglobin index (nTHI) and tissue oxygenation index (TOI) were measured after posture variations. RESULTS: No statistically significant changes in nTHI and in TOI were found in the 6 postures. nTHI variations, expression of cerebral blood volume variations, were influenced by GA. A reduction in nTHI, with a stable TOI, in the less mature infants (with GA < or = 26 weeks), occurred on head rotation; nTHI increased again when the head was derotated. CONCLUSIONS: Hemodynamic changes after posture variations depend on GA. Head rotation in newborns with GA < or = 26 weeks produced a reduction in nTHI with stable TOI. Possible physiopathological mechanisms are discussed.

Changes in cerebral hemodynamics and amplitude integrated EEG in an asphyxiated newborn during and after cool cap treatment.

Amplitude integrated EEG (aEEG) and Near Infrared Spectroscopy (NIRS) were applied in a newborn with a moderate hypoxic-ischemic encephalopathy before, during and after brain cooling. At 2h of life a selective head cooling with mild systemic hypothermia was started and maintained for 72h. aEEG background pattern improved from severely abnormal to normal during the first 17h of life. NIRS revealed a reduction in cerebral blood volume (CBV) during hypothermia that recovered during the rewarming period, whereas brain oxygenation remained stable. As brain cooling is supposed to reduce delayed hyperemia and help to maintain neuronal metabolism following cerebral insults, aEEG and NIRS monitoring may be useful during hypothermic treatment in order to document changes in CBV and brain oxygenation possibly reflecting the efficacy of hypothermia.