Review shows that using surfactant a number of times or as a vehicle for budesonide may reduce the risk of bronchopulmonary dysplasia.

AIM: Bronchopulmonary dysplasia (BPD) remains the most common respiratory morbidity in immature infants. This review describes the diagnosis of BPD has evolved and summarises the therapeutic approaches that have made it possible to limit the incidence of BPD. METHOD: We reviewed the literature from the first definition of BPD by Northway in 1967 to the surfactant treatment policies that are currently in use, drawing on more than 50 papers up to 2017. RESULTS: Our review showed that improvements in neonatal survival have been associated with an increased risk of severe BPD, significant levels of long-term morbidity and the increased use of healthcare resources. These issues have encouraged researchers to explore potential new treatments that limit the incidence of BPD. Repeated surfactant instillation and the use of surfactant as a vehicle for budesonide are promising strategies for alleviating the burden of chronic lung disease. Ongoing research on surfactant or stem cell therapy may further improve the respiratory prognosis for prematurely born children. CONCLUSION: Considerable research has been carried out into the increase in BPD, which has resulted from improvements in neonatal survival. Key areas of research include repeated surfactant administration, using surfactant as a vehicle for budesonide and stem cell therapy.

Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants.

BACKGROUND: Inhaled nitric oxide (iNO), commonly used for hypoxic neonates, may react with haemoglobin to form methaemoglobin (MetHb). MetHb monitoring during iNO therapy has been questioned since low doses of iNO are used. AIM: To evaluate the incidence of and identify risk factors associated with elevated MetHb in neonates treated with iNO. METHODS: Neonates who were treated with iNO and had at least one MetHb measurement were included. Demographic characteristics and methods of iNO administration (dosage, duration) at the time of each MetHb measurement were analysed. RESULTS: Four hundred and fifty-two MetHb measurements from 81 premature and 82 term and near-term infants were analysed. MetHb was above 5% in one-term infant, and between 2.5-5% in 16 infants. A higher maximum dose of iNO (22.7 vs 17.7 p.p.m.), but not gestational age, was a significant risk factor for elevated MetHb. Significantly higher oxygen levels (75.5% vs 51.7%) were associated with higher MetHb in term infants. Preterm infants had no risk for high MetHb when iNO was kept below 8 p.p.m. These data suggest the possibility of limiting blood withdrawal when low doses iNO are used. CONCLUSION: High MetHb is exceptional in neonates treated with low dose iNO. Associated risk factors are related to high iNO dose and the simultaneous use of high concentrations of oxygen.

[Neonatal Bartter syndrome's special features in very premature newborns]. / Particularités diagnostiques du syndrome de Bartter néonatal chez le nouveau-né grand prématuré

Neonatal Bartter syndrome is a rare condition, usually revealed by alkalosis and hypokalemia. Clinical and biological signs of neonatal Bartter syndrome are quite different from those encountered when this disease is diagnosed in older children. Diagnosis of neonatal Bartter syndrome is even more difficult in very preterm infants. The aim of this study was to highlight specific clinical and biological signs that may help direct physicians towards the diagnosis of neonatal Bartter syndrome when premature infants present with an atypical renal tubular disorder. Our case reports focus on excessive diuresis with elevated renal sodium excretion and severe dehydration. Correcting tubular disorders early may help avoid dehydration in the fragile preterm newborn.

Sheep lung cytochrome P4501A1 (CYP1A1): cDNA cloning and transcriptional regulation by oxygen tension.

Lung cytochrome P450 activity has been linked to neoplasia and may produce reactive oxidant species and potent arachidonic acid metabolites. In lamb lung, oxygen breathing increases lung P450 activity, and inhibition of lung cytochrome P450 activity reduces oxygen-induced lung injury. The P4501A1 (CYP1A1) isozyme is present in many lung cells, including endothelial cells, and may therefore be involved in the pathogenesis of hyperoxic injury to microvascular endothelium. Therefore, to test the hypothesis that oxygen regulates P4501A1 gene expression in the lung, we cloned the sheep P4501A1 cDNA, and examined its regulation by oxygen breathing significantly increased lung P4501A1 RNA levels and that this increase preceded the increase in isozyme activity. Oxygen exposure also promptly increased P4501A1 RNA levels in cultured lamb lung microvascular endothelial cells but not in endothelial cells isolated from the main pulmonary artery or in lung smooth muscle cells. The oxygen-stimulated increase in P4501A1 RNA levels was not serum dependent, was unaffected by cycloheximide treatment, and could not be mimicked by treatment of the cells with oxygenated medium, conditioned medium, or by chemical oxidants. By nuclear run-on assay in cultured lung endothelial cells, oxygen increased the transcription rate of P4501A1 by almost fourfold after 90 min of oxygen exposure but had no significant effect on P4501A1 RNA stability. We conclude that oxygen tension, but not chemical oxidants, increases P4501A1 gene expression pretranslationally in lung microvascular endothelial cells. We speculate that oxygen induction of P450 activity in these cells may contribute to microvascular injury during oxygen breathing.

[Secondary right-sided diaphragmatic hernia following neonatal group B Streptococcal septicaemia in a preterm infant]. / Hernie diaphragmatique droite à révélation secondaire et septicémie néonatale à Streptocoque B chez un prématuré.

We report on a case of a secondary right-sided diaphragmatic hernia following group B streptococcal (GBS) septicaemia in a very low birth weight infant born at 30 weeks. After initial improvement, the diagnosis of a secondary right-sided diaphragmatic hernia was suspected with the persistent radiological pulmonary right-sided image on the chest x-ray and the clinical degradation. The diagnosis was confirmed by ultrasonography on day 43. The postoperative course was simple. Persistent respiratory distress in a neonate, after a GBS septicaemia associated with a right pulmonary opacity on the chest x-ray, should prompt a careful evaluation. A secondary right-sided diaphragmatic hernia should be considered. Treatment is surgery, the prognosis is good in the absence of pulmonary hypoplasia.

Growth and neurodevelopment outcome in symmetric versus asymmetric small for gestational age term infants.

OBJECTIVE: Few studies compared growth and neurodevelopment outcome between asymmetric (aSYM) and symmetric (SYM) small for gestational age (SGA) term infants. We aimed at evaluating their respective outcome at 9 months postnatal age. STUDY DESIGN: A cohort study including infants born in 2010 to 2011 with a birth weight <5th centile and a head circumference (HC) below (SYM) or above (aSYM) the 5th centile. Catch-up growth was defined as weight, height and HC ⩾-2 s.d. of World Health Organization reference values. Neurodevelopment was evaluated with Brunet-Lezine test items. RESULT: Of 6586 infants, 194 were SGA: 38.7% SYM and 61.3% aSYM. The aSYM group showed better catch-up growth (85% versus 70%, P=0.03) with larger HC (44.9±1.6 versus 43.7±1.2 cm, P<0.0001). No difference in neurodevelopmental screening was observed between SGA groups, but infants without any catch-up growth were at higher risk of delayed outcome. CONCLUSION: Term SGA infants must be closely followed, regardless of their characteristics, to improve their outcome.

Doxapram Dosing for Apnea of Prematurity Based on Postmenstrual Age and Gender: A Randomized Controlled Trial.

INTRODUCTION: Doxapram is used as a third-line treatment for apnea unresponsive to caffeine and continuous positive airway pressure (CPAP) in preterm infants. OBJECTIVES: The objectives of this study were to compare the effects of dosing adjusted for gender and postmenstrual age (PMA) (GrA) versus infants' weight alone (GrW) on doxapram plasma levels, clinical efficacy, and side effects. METHODS: This was a randomized, double-blind study, including premature infants for whom optimized caffeine and CPAP therapy for apnea of prematurity had failed. Failure was defined as the persistence of more than one significant apnea per hour over an 8-h period. Plasma levels of doxapram and ketodoxapram were measured with high-performance liquid chromatography (HPLC) 48 h after the onset of treatment. Dosing aimed to maintain the combined doxapram and ketodoxapram plasma level in the therapeutic range of 1.5-4 mg/l. Infants were followed-up for 4 days after the onset of treatment. RESULTS: A total of 85 infants were included: 46 in GrW (27.7 ± 1.9 weeks' gestational age [GA]), 39 in GrA (27.9 ± 1.4 weeks' GA); available plasma levels showed that 25 of 40 in the GrW group and 27 of 37 in the GrA group had levels within the therapeutic range (p = 0.344). Of note, plasma level variance was significantly higher in GrW for doxapram + ketodoxapram (1.87 vs. 0.89; p = 0.028). Clinical efficacy was better in the GrA group, with a reduction from 32 to 3 of 38 (76 %) infants with significant apnea versus 30 to 5 of 45 (56 %) in the GrW group (p < 0.001). No adverse effects were observed during the study. CONCLUSIONS: Taking gender and PMA into account for doxapram dosing did not significantly increase the number of infants with a plasma level in the therapeutic range. However, it improved plasma level stability and clinical efficacy without adverse effects. ClinicalTrials.gov number: NCT00389909.

Risks and benefits of therapies for apnoea in premature infants.

Apnoea in infants can result from a wide range of causes, and requires thorough evaluation before deciding on appropriate treatment. Continuous monitoring of premature infants with apnoea is mandatory in order to define the pathophysiology and type of apnoea; selection of treatment involves careful assessment of aetiology, as well as efficacy and tolerability in each individual case. The objective of treatment is to prevent the deleterious consequences of apnoeas that last >20 seconds and/or are associated with bradycardia, cyanosis or pallor, and occur more often than once an hour over a 12-hour period. Apnoea management involves both pharmacological and nonpharmacological treatment. We suggest methylxanthines as first-line therapy for idiopathic apnoeas; evidence suggests that caffeine is better tolerated and as efficacious as theophylline (since it is particularly efficacious against the 'central' component of idiopathic apnoea of prematurity). If treatment fails, additional measures such as doxapram may be appropriate when hypoventilation is present, or nasal continuous positive airway pressure when upper airway instability or obstructive apnoeas are predominant. Apnoea prophylaxis is an additional reason to advocate prenatal maturation with betamethasone. Weaning from treatment is attempted 4 to 5 days after complete resolution of apnoea, beginning with the last treatment introduced. Monitoring should be maintained for 4 to 5 days to detect any relapse of recurrent and severe apnoeas, which would lead to the resumption of the most recently withdrawn treatment.

Analgesia after caesarean section: patient-controlled intravenous morphine vs epidural morphine.

In a randomized, double-blind study, conducted in 60 patients after caesarean section, we compared epidural morphine (5 mg) with intravenous morphine patient-controlled analgesia (PCA). Efficacy of pain relief (visual analogue scale), comfort, satisfaction and side-effects were studied. In the PCA group, pain scores were higher (P < 0.005) from the third hour onward. The degree of comfort was similar. Overall satisfaction for the first 24 postoperative hours was higher in the epidural group when assessed on a graded scale from 0 to 10, but equal when assessed using qualitative terms. Haemodynamic and respiratory tolerance were identical without any episodes of respiratory depression or oxygen desaturation in either group. The epidural morphine group showed a higher incidence of pruritus requiring specific treatment (P < 0.005). Nausea was reported to be equal in the two groups. Consumption of morphine was higher in the PCA group. We conclude that epidural morphine analgesia, though of good quality, was associated with more pruritus. Morphine PCA, although producing a lesser degree of analgesia compared to epidural morphine, gave good satisfaction.

[Liquid ventilation: a new mode of ventilation in neonatology?]. / La ventilation liquide: nouveau mode de ventilation en néonatologie?

Liquid ventilation is based on perfluorocarbons capacity to transport O2 and CO2. Almost 30 years of experimental studies have shown its feasibility and high performances. Results of the first clinical applications in severe neonatal respiratory failure are encouraging. Results of larger randomized and controlled studies, actually in preparation, are awaited with interest.

[Anatomical route of pain in premature newborn infants]. / Voies anatomiques de la douleur chez le nouveau-né prématuré.

Recent research about nociceptive pathways in newborn infants have shown that, even very immature, preterm infants have all the anatomical and functional components required for the perception of painful stimuli. However, the perception of pain in preterm infants is thought to be slightly different from that of term infants: because of a lack of myelination of their sensitive fibers and a still immature cortical organization of the somatosensory system, painful stimuli are perceived more widespread and durable. In addition, the threshold of pain seems to be lower in premature infants, probably due to a lack of protection of their spinal and supraspinal inhibitory pathways. Finally, abnormal behavioural imprinting secondary to early painful stimuli is now suggested. Thus in contrast with the former misconception of "insensitivity towards pain", premature infants must be now considered as "hypersensitive" and vulnerable.

[Management of severe neonatal Rh disease following in utero exchange transfusion: towards a new strategy]. / Prise en charge néonatale des allo-immunisations Rhésus sévères après exsanguinotransfusion in utero: vers une nouvelle stratégie.

Important changes in the prevention, diagnosis, and in utero treatment, of Rhesus allo-immunization in the past 30 years, have led to new neonatal clinical presentations. Based upon the analysis of 14 successive pregnancies with severe hemolytic disease, requiring in utero exchange-transfusion, it appears that the current management is no longer adapted to the new resulting clinical postnatal presentations. In the acute phase, intensive phototherapy associated with regular blood cell transfusion as required, appears to be a better policy than traditional postnatal systematic exchange transfusions. In addition endogenous erythropoiesis stimulation should be included in order to avoid any unnecessary transfusion.

[Massive fetomaternal transfusion after induction of labor by oxytocin]. / Transfusion foetomaternelle massive au décours de l'induction du travail par ocytocique.

UNLABELLED: Severe fetomaternal transfusions are seldom, but may lead to neonatal morbidity or death. CASE REPORT: We report a case of lethal fetomaternal transfusion in which a failure to induce labour, at term, can be suspected. COMMENTS: We emphasize the need of a close monitoring of the fetal well-being in cases of failed induced labour at term.

[Sudden death of neonates in the delivery room]. / Mort de nouveau-nés apparemment sains en salle de naissance: un problème de surveillance?

Healthy newborn death in the delivery room is uncommon. Unlike for sudden infant death syndrome well described in infants between 2 and 6 months of age, few publications have studied this event. We report two cases of asymptomatic term newborns who died unexpectedly in the delivery room. Noteworthy, these newborns were sleeping in prone position on their mother. The Agence Nationale d'Accreditation et d'Evaluation en Sante (ANAES) published recommendations to promote breast-feeding including uninterrupted early contact between the infant and his mother. However, immediately after birth, the newborn may be particularly vulnerable. The application of this recommendation unwisely could be dangerous for newborns allowed to stay on their mother without any monitoring, or medical supervision. We would like to point out the importance of healthy newborn supervision within the first hours of life that can be done without interfering with the mother-child bonding.

[Efficacy and limits of rescue high-frequency oscillatory ventilation in the treatment of hyaline membrane disease in preterm newborns]. / Efficacité et limites de la ventilation par oscillations à haute fréquence après échec de la ventilation conventionnelle chez des prématurés atteints de maladie des membranes hyalines sévère.

UNLABELLED: Conflicting reports of high-frequency oscillatory ventilation (HFOV) use as an alternative to conventional mechanical ventilation have been published. This retrospective study has evaluated the efficacy and safety of rescue HFOV in preterm infants with severe hyaline membrane disease (HMD) after the failure of conventional mechanical ventilation (CMV). POPULATION AND METHODS: All newborns hospitalized in our neonatal intensive care unit (NICU) from 10.1.1993 to 15.4.1995 with CMV failure, defined as the need for more than 55% FiO2 without any improvement for at least six hours, have been retrospectively studied. The infants were shared according to the absence (Gr I) or the presence (Gr II) of persistent pulmonary hypertension of neonate (PPHN) in addition to HMD before HFOV. RESULTS: Gestational age (GA) was 29.2 +/- 3.7 weeks (mean +/- SD) in Gr I and 30.3 +/- 2.8 in Gr II. Birth weight was 1379 +/- 750 g and 1471 +/- 612 g, respectively. As soon as three hours after the onset of HFOV in both groups, a dramatic improvement was observed with a FiO2 drop from 82 +/- 20% to 64.8 +/- 25.5% (P < 0.01). Among the infants, 62% survived without any major disability and 28% died (46% in Gr II vs 12% in Gr I, P < 0.01). A trend towards a worsening of pre-existing brain lesions has been noticed. An increased risk of mortality was observed when a secondary worsening in O2 requirements occurred 24 hours after the onset of HFOV, despite an initial significant improvement. SGA was also associated with a poor prognosis (46% of the deaths vs 29% for AGA infants, P < 0.05). CONCLUSION: HFOV has been successfully used in premature infants with severe respiratory disease and failure of CMV. Criteria of poor prognosis were PPHN and SGA, or a secondary worsening in oxygen requirements after initial improvement. A trend towards aggravation of pre-existing brain lesions has been noticed after HFOV. This aggravation is more frequent when PPHN is associated with HMD. This observation suggests caution for HFOV use when these conditions are present in premature infants.

[Perinatal corticotherapy: updates]. / La corticothérapie périnatale: actualités.

The beneficial effects of antenatal corticosteroid treatment are now well established. Likewise, a functional pulmonary improvement has been demonstrated when corticosteroids are used in neonates with chronic lung disease. However, several questions remain to be answered. This review of recent data suggest the need for an updated policy of treatment to improve prognosis. In our population, antenatal maturation has reached a level of 77% below 32 weeks gestation and is associated with a 50% reduction of the risk of severe respiratory distress syndrome. Antenatal steroids have been shown to be beneficial as soon as 23 weeks gestation, but the indication for treatment needs to be carefully evaluated since side effects appear to overcome benefits above 3 repeated courses of treatment. An optimal interval between each course can be set at 10 to 15 days according to the severity of premature labor and gestational age. Since several experimental and clinical studies suggest an increased risk of neurological disability with dexamethasone as compared with betamethasone, it seems consistent to favor the exclusive use of antenatal betamethasone as well as its postnatal choice when indicated. Postnatal use should be restricted to severe chronic lung disease and pulse therapy is now the optimal choice to reduce side effects.

[Limits of antenatal management: technical and ethical aspects]. / Limites de la prise en charge anténatale: aspects techniques et éthiques.

The lower limit for elective delivery depends on technical and ethical issues. Elective delivery is usually accepted after 26 weeks gestation with a 60% survival rate and a 30% handicap rate. Decision making requires close coordination between obstetricians and pediatricians. Sufficient time must be devoted to providing the parents with adequate information. The physician plays a crucial role in decision making, but parent's information and consent are essential.

[Neonatal therapeutic hypothermia: amplitude-integrated electroencephalography to confirm the indication]. / Hypothermie thérapeutique contrôlée pour asphyxie périnatale : intérêt de l'électroencéphalogramme d'amplitude pour évaluer l'indication.

Moderate hypothermia therapy (HT) after perinatal asphyxia of the newborn has clearly demonstrated its efficacy in reducing both mortality and long-term neurosensory sequelae. HT has now been introduced in many developed countries as a standard of care for term infants meeting the entry criteria for therapeutic cooling. However, this new therapy is only effective in case of an acute perinatal hypoxic-ischemic event. Since a number of potentially deleterious complications have been described during cooling, a strict evaluation of the newborn's status is mandatory. To help clinicians reliably select newborns who may benefit from HT, amplitude-integrated electroencephalography (aEEG) is today strongly recommended. The indication criteria for cooling include aEEG in addition to delivery history, Apgar score, cord pH and lactates, and neurological scoring for encephalopathy. We report a clinical case of a term baby girl, considered for HT in our unit, because of a clinical feature of severe neonatal encephalopathy, metabolic acidosis on cord pH, and a history of fetal distress on fetal heart rate monitoring. However, despite all these criteria, her early aEEG, like her classic EEG, showed no signs of hypoxic-ischemic encephalopathy (HIE). She was then denied HT and her early magnetic resonance imaging (MRI) exam showed no signs of HIE but typical features of a metabolic disorder (Zellweger-like syndrome). Thanks to the HT strict protocols, including early aEEG and MRI exam, the right diagnosis was rapidly made and the hypothesis of a hypoxic-ischemic event during delivery was finally ruled out.

[Gender-dependent differences in glutathione (GSH) metabolism in very preterm infants]. / Différences liées au sexe dans le métabolisme du glutathion (GSH) du grand prématuré

BACKGROUND: Gender differences in mortality and morbidity are often reported in very preterm infants. In studies aiming to understand the underlying mechanisms, better protection against oxidative stress in baby girls has been suggested. OBJECTIVES: Shortly after birth, we compared glutathione (GSH) metabolism in female and male preterm infants and its relationship with prenatal and postnatal parameters. METHODS: We took the opportunity of a prospective randomised controlled trial evaluating the safety-efficacy balance of inhaled nitric oxide (Hamon and al., 2005) [12] to assess, in vivo, the antioxidant defences within the first 48 h of life in 240 premature infants less than 32 weeks gestational age (GA). We measured total plasmatic GSH level (nmol/L), intraerythrocyte glutathione peroxidase (GPX, µmol/min/g haemoglobin) and intraerythrocyte glutathione reductase (GR, µmol/min/g haemoglobin) from venous blood samples withdrawn through central lines. RESULTS: Expressed as mean ± standard error of the mean: soon after birth (at 24h median), plasmatic GSH was not different between females (n=123) and males (n=117): 0.932 ± 0.016 vs 0.956 ± 0.012 nmol/L. However, at the same time, GPX, the enzyme involved in GSH synthesis, was at a significantly higher level in baby girls (p<0.001): 11.63 ± 0.25 vs 10.21 ± 0.24 µmol/min/g haemoglobin, as was GR, the enzyme responsible for GSH regeneration (p=0.02): 12.18 ± 0.23 vs 11.22 ± 0.21 µmol/min/g haemoglobin. We observed no significant correlation between GSH levels, GPX, or GR activities with prenatal steroids, GA, birth weight, severity of respiratory disease, and oxygen requirements for the entire population or between the two genders. CONCLUSION: Whereas the level of glutathione, a key molecule in the defence against oxidative stress in humans, appears to be identical in preterm females and males soon after birth, the enzymes involved in its synthesis (GPX) and regeneration (GR) are higher in females. SPECULATION: Study of the sequential progression of GSH, GPX, and GR with regard to prolonged oxidative stress exposure in preterm females and males is needed to better evaluate their potential clinical relevance.