High vs. Low Initial Oxygen to Improve the Breathing Effort of Preterm Infants at Birth: Study Protocol for a Randomized Controlled Trial

Background: Although most preterm infants breathe at birth, their respiratory drive is weak and supplemental oxygen is often needed to overcome hypoxia. This could in turn lead to hyperoxia. To reduce the risk of hyperoxia, currently an initial low oxygen concentration (21–30%) is recommended during stabilization at birth, accepting the risk of a hypoxic period. However, hypoxia inhibits respiratory drive in preterm infants. Starting with a higher level of oxygen could lead to a shorter duration of hypoxia by stimulating breathing effort of preterm infants, and combined with subsequent titration based on oxygen saturation, prolonged hyperoxia might be prevented.Study design: This multi-center randomized controlled trial will include 50 infants with a gestational age between 24 and 30 weeks. Eligible infants will be randomized to stabilization with an initial FiO2 of either 1.0 or 0.3 at birth. Hereafter, FiO2 will be titrated based on the oxygen saturation target range. In both groups, all other interventions during stabilization and thereafter will be similar. The primary outcome is respiratory effort in the first 5 min after birth expressed as average minute volume/kg. Secondary outcomes include inspired tidal volumes/kg, rate of rise to maximum tidal volume/kg, percentage of recruitment breaths with tidal volumes above 8 mL/kg, duration of hypoxia and hyperoxia and plasma levels of markers of oxidative stress (8-iso-prostaglandin F2α).Discussion: Current resuscitation guidelines recommend oxygen titration if infants fail to achieve the 25th percentile of the SpO2 reference ranges. It has become clear that, using this approach, most preterm infants are at risk for hypoxia in the first 5 min after birth, which could suppress the breathing effort. In addition, for compromised preterm infants who need respiratory support at birth, higher SpO2 reference ranges in the first minutes after birth might be needed to prevent prolonged hypoxia. Enhancing breathing effort by achieving an adequate level of oxygenation could potentially lead to a lower incidence of intubation and mechanical ventilation in the delivery room, contributing to a lower risk on lung injury in high-risk preterm infants. Measuring 8-iso-prostaglandin F2α could lead to a reflection of the true amount of oxygen exposure in both study groups

Increasing Respiratory Effort With 100% Oxygen During Resuscitation of Preterm Rabbits at Birth

Background: Spontaneous breathing is essential for successful non-invasive respiratory support delivered by a facemask at birth. As hypoxia is a potent inhibitor of spontaneous breathing, initiating respiratory support with a high fraction of inspired O2 may reduce the risk of hypoxia and increase respiratory effort at birth. Methods: Preterm rabbit kittens (29 days gestation, term ~32 days) were delivered and randomized to receive continuous positive airway pressure with either 21% (n = 12) or 100% O2 (n = 8) via a facemask. If apnea occurred, intermittent positive pressure ventilation (iPPV) was applied with either 21% or 100% O2 in kittens who started in 21% O2, and remained at 100% O2 for kittens who started the experiment in 100% O2. Respiratory rate (breaths per minute, bpm) and variability in inter-breath interval (%) were measured from esophageal pressure recordings and functional residual capacity (FRC) was measured from synchrotron phase-contrast X-ray images. Results: Initially, kittens receiving 21% O2 had a significantly lower respiratory rate and higher variability in inter-breath interval, indicating a less stable breathing pattern than kittens starting in 100% O2 [median (IQR) respiratory rate: 16 (4–28) vs. 38 (29–46) bpm, p = 0.001; variability in inter-breath interval: 33.3% (17.2–50.1%) vs. 27.5% (18.6–36.3%), p = 0.009]. Apnea that required iPPV, was more frequently observed in kittens in whom resuscitation was started with 21% compared to 100% O2 (11/12 vs. 1/8, p = 0.001). After recovering from apnea, respiratory rate was significantly lower and variability in inter-breath interval was significantly higher in kittens who received iPPV with 21% compared to 100% O2. FRC was not different between study groups at both timepoints. Conclusion: Initiating resuscitation with 100% O2 resulted in increased respiratory activity and stability, thereby reducing the risk of apnea and need for iPPV after birth. Further studies in human preterm infants are mandatory to confirm the benefit of this approach in terms of oxygenation. In addition, the ability to avoid hyperoxia after initiation of resuscitation with 100% oxygen, using a titration protocol based on oxygen saturation, needs to be clarified

Regulation of fetal lung development in response to maternal overnutrition

With the worldwide obesity epidemic, the proportion of women entering pregnancy overweight or obese has increased significantly in recent years. Babies born to obese women are at an increased risk of respiratory complications at birth and in childhood. In addition to maternal diabetes, there are a number of metabolic changes that the fetus of an overnourished mother experiences in utero that may modulate lung development and represent the mechanisms underlying the increased risk of respiratory complications. Herein we highlight a series of factors associated with the intrauterine environment of an overnourished mother that may impact on fetal lung development and lead to an increased risk of complications at birth or in postnatal life.

Editorial: Visibility matters – women in neonatology

We are delighted to present the inaugural Frontiers in Pediatrics Women in Neonatology series. Gender inequity in health and medical research has been perpetuated by longstanding biases (including unconscious bias), stereotypes and structural barriers to the recruitment, retention, career progression and recognition of women’s achievements. While many structural changes are required to address these factors towards achieving equity, active allyship and visibility is also important to support and encourage the next generation of women and girls to pursue research careers. This article collection includes 5 original research papers, 2 brief research reports and 1 review article demonstrating a diversity of neonatology-related research led by women. Depicolzuane et al. reviewed and presented a summary of animal and translational studies, and clinical observations on the role of lung surfactant protein A in lung function and importantly in lung protection from both infectious and non-infectious agents. Surfactant protein A has a unique role in the lung through its interactions with lung macrophages where it impacts the activity of alveolar macrophages in response to injurious agents or stimuli. Interestingly, surfactant protein A also has a role in control of the in utero environment

Supporting breathing of preterm infants at birth: a narrative review

Most very preterm infants have difficulty aerating their lungs and require respiratory support at birth. Currently in clinical practice, non-invasive ventilation in the form of continuous positive airway pressure (CPAP) and positive pressure ventilation (PPV) is applied via facemask. As most very preterm infants breathe weakly and unnoticed at birth, PPV is often administered. PPV is, however, frequently ineffective due to pressure settings, mask leak and airway obstruction. Meanwhile, high positive inspiratory pressures and spontaneous breathing coinciding with inflations can generate high tidal volumes. Evidence from preclinical studies demonstrates that high tidal volumes can be injurious to the lungs and brains of premature newborns. To reduce the need for PPV in the delivery room, it should be considered to optimise spontaneous breathing with CPAP. CPAP is recommended in guidelines and commonly used in the delivery room after a period of PPV, but little data is available on the ideal CPAP strategy and CPAP delivering devices and interfaces used in the delivery room. This narrative review summarises the currently available evidence for why PPV can be inadequate at birth and what is known about different CPAP strategies, devices and interfaces used the delivery room

Evaluating Clinical Outcomes and Physiological Perspectives in Studies Investigating Respiratory Support for Babies Born at Term With or at Risk of Transient Tachypnea: A Narrative Review

Respiratory distress in the first few hours of life is a growing disease burden in otherwise healthy babies born at term (>37 weeks gestation). Babies born by cesarean section without labor (i.e., elective cesarean section) are at greater risk of developing respiratory distress due to elevated airway liquid volumes at birth. These babies are commonly diagnosed with transient tachypnea of the newborn (TTN) and historically treatments have mostly focused on enhancing airway liquid clearance pharmacologically or restricting fluid intake with limited success. Alternatively, a number of clinical studies have investigated the potential benefits of respiratory support in newborns with or at risk of TTN, but there is considerable heterogeneity in study designs and outcome measures. A literature search identified eight clinical studies investigating use of respiratory support on outcomes related to TTN in babies born at term. Study demographics including gestational age, mode of birth, antenatal corticosteroid exposure, TTN diagnosis, timing of intervention (prophylactic/interventional), respiratory support (type/interface/device/pressure), and study outcomes were compared. This narrative review provides an overview of factors within and between studies assessing respiratory support for preventing and/or treating TTN. In addition, we discuss the physiological understanding of how respiratory support aids lung function in newborns with elevated airway liquid volumes at birth. However, many questions remain regarding the timing of onset, pressure delivered, device/interface used and duration, and weaning of support. Future studies are required to address these gaps in knowledge to provide evidenced based recommendations for management of newborns with or at risk of TTN

Antenatal Steroids and the IUGR Fetus: Are Exposure and Physiological Effects on the Lung and Cardiovascular System the Same as in Normally Grown Fetuses?

Glucocorticoids are administered to pregnant women at risk of preterm labour to promote fetal lung surfactant maturation. Intrauterine growth restriction (IUGR) is associated with an increased risk of preterm labour. Hence, IUGR babies may be exposed to antenatal glucocorticoids. The ability of the placenta or blood brain barrier to remove glucocorticoids from the fetal compartment or the brain is compromised in the IUGR fetus, which may have implications for lung, brain, and heart development. There is conflicting evidence on the effect of exogenous glucocorticoids on surfactant protein expression in different animal models of IUGR. Furthermore, the IUGR fetus undergoes significant cardiovascular adaptations, including altered blood pressure regulation, which is in conflict with glucocorticoid-induced alterations in blood pressure and flow. Hence, antenatal glucocorticoid therapy in the IUGR fetus may compromise regulation of cardiovascular development. The role of cortisol in cardiomyocyte development is not clear with conflicting evidence in different species and models of IUGR. Further studies are required to study the effects of antenatal glucocorticoids on lung, brain, and heart development in the IUGR fetus. Of specific interest are the aetiology of IUGR and the resultant degree, duration, and severity of hypoxemia

Efficacy of Intravenous, Endotracheal, or Nasal Adrenaline Administration During Resuscitation of Near-Term Asphyxiated Lambs

Objectives: Neonatal resuscitation guidelines recommend administering intravenous (IV) adrenaline if bradycardia persists despite adequate ventilation and chest compressions (CC). Rapid IV access is challenging, but little evidence exists for other routes of administration. We compared IV, endotracheal (ET), and intranasal routes for adrenaline administration during resuscitation of asphyxiated newborn lambs. Study design: Near-term lambs (n = 22) were delivered by caesarean section. Severe asphyxia was induced by clamping the umbilical cord while delaying ET ventilation until blood flow in the carotid artery ceased. Following a 30 s sustained inflation and ventilation for 30 s, we commenced uncoordinated CC at 90/min. We randomized four groups receiving repeated treatment doses (Tds) every 3rd min of (i) IV-Adrenaline (50 μg), (ii) ET-Adrenaline (500 μg), (iii) Nasal-Adrenaline via an atomizer (500 μg), and (iv) IV-saline. If return of spontaneous circulation (ROSC) was not achieved after three Tds by the assigned route, up to two rescue doses (Rds) of IV adrenaline were administered. Main outcome measures were achievement of ROSC and time from start of CC to ROSC, defined as heart rate >100/min, and mean carotid arterial pressure >30 mmHg. Results: In the IV-Adrenaline group, 5/6 lambs achieved ROSC after the first Td, whereas 1 lamb required two Tds before achieving ROSC. In the ET-Adrenaline group, 1/5 lambs required one Td, 1 lamb required three Tds, 2 lambs required 2 Rds, and 1 did not achieve ROSC. In the Nasal-Adrenaline group, 1/6 lambs required one Td, 2 required two Tds, whereas 3 lambs required either one (2 lambs) or two (1 lamb) Rds of adrenaline to achieve ROSC. In the IV-saline group, no lambs achieved ROSC until adrenaline Rds; 4/5 lambs required one Rd and 1 lamb required two Rds. Time to ROSC was shorter using IV-Adrenaline (2.4 ± 0.4 min) compared with ET-Adrenaline (10.3 ± 2.4 min), Nasal-Adrenaline (9.2 ± 2.2 min), and IV-saline (11.2 ± 1.2 min). Conclusion: IV adrenaline had superior efficacy compared with nasal or ET administration. Nasal administration had a similar effect as ET administration and is an easier route for early application. Nasal high-dose adrenaline administration for neonatal resuscitation merits further investigation