KEY POINTS
- 1.
There is a precisely controlled sequence of circulatory and respiratory changes at birth that leads to the establishment of adult-type circulation and airborne respiration.
- 2.
Despite the well-established sequence of events, 1 in 10 infants, particularly those born before term, will require interventions to achieve an adequate postnatal adaptation.
- 3.
Oxygen has been widely accepted as the most relevant drug for preterm resuscitation.
- 4.
There is a need to achieve oxygen saturation between 80% and 85% within the first 5 minutes after birth in very preterm infants <32 weeks’ gestation) independently of the initial fraction of inspired oxygen.
- 5.
We need continued and critical appraisal of both the need for and the doses (concentrations) of oxygen administered during resuscitation.
Introduction
Fetal-to-neonatal transition in mammals is characterized by a precise sequence of circulatory and respiratory changes that contribute to the establishment of adult-type circulation and airborne respiration. As a consequence, there is an abrupt increase in the oxygen availability that fulfills the increased energy requirements of multicellular organisms. Despite the exquisite physiologic arrangements that regulate this sequence of events, almost 10% of all newly born infants, and especially those born prematurely, require resuscitative interventions to achieve an adequate postnatal adaptation. In the newborn period, resuscitation requires lung expansion, reducing pulmonary resistance, improving lung compliance, and achieving a functional residual capacity. All these changes improve alveolar capillary gas exchange and arterial blood oxygenation.
The lungs, the thoracic cage, and respiratory muscles mature late in gestation. Moreover, surfactant and the antioxidant enzymatic and nonenzymatic defenses, especially in males, are not readily available until the last weeks of gestation. Hence preterm infants, especially very preterm infants with a gestational age (GA) below 32 weeks, frequently experience difficulties establishing effective respiration immediately after birth. Immaturity and surfactant deficiency lead to uneven lung ventilation with hyperventilated areas coexisting with atelectasis and the inability to establish a functional residual capacity. As a consequence, the premature baby is at increased risk of developing hypoxemia, hypercapnia, and increased work of breathing, which are characteristic of respiratory distress syndrome with hypoxemic respiratory failure. Therefore prenatal interventions such as the administration of antenatal steroids and postnatal resuscitation with positive pressure ventilation and oxygen supplementation constitute essential interventions necessary to overcome respiratory insufficiency.
Oxygen has been widely accepted as the most relevant drug for preterm resuscitation. However, there are still important aspects regarding its use in the immediate postnatal period that have not yet been answered. It is necessary to address the optimal initial fraction of inspired oxygen (Fi o 2 ), oxygen saturation (Sp o 2 ) target ranges in the first minutes after birth, and how to titrate oxygen according to the infant’s response. Of note, oxygen in excess leads to hyperoxemia and direct tissue damage secondary to oxidative stress, activation of proinflammatory and proapoptotic pathways, and other mechanisms. At the other extreme, hypoxemia, especially when combined with bradycardia, significantly enhances the risk for intraventricular hemorrhage (IVH) and death. Both situations increase mortality and/or short- to long-term morbidities in survivors.
The aim of the present chapter is to critically analyze the most relevant and recent literature concerning the use of oxygen in the delivery room (DR) to help neonatologists optimize the care management of preterm infants during postnatal stabilization.
Oxygen in Utero and During Fetal-to-Neonatal Transition
During late gestation, the arterial partial pressure of oxygen ranges between from 25 to 30 mm Hg in the fetus and 80 to 90 mm Hg in the mother. The oxygen gradient between the mother and fetus drives oxygen across the intervillous space of the placenta. The oxygen content in fetal blood is low during embryogenesis and progressively rises during fetogenesis, reaching a saturation plateau of 50% to 60% at approximately 14 to 20 weeks after conception. Thereafter, Sp o 2 slowly decreases to values of 45% to 50% in the last trimester. Oxygenated blood is redirected through circulatory shunts at the foramen ovale and ductus arteriosus to the lung, brain, and cardiac circulation. The brain and heart are extremely dependent on aerobic metabolism. Immediately after birth, newly born infants initiate profound inspiratory movements, reaching negative pressures of as low as −40 to −50 cm H 2 O that contribute to lung expansion and extrusion of lung fluid from the respiratory airways and alveoli to the interstitium. In addition, increased oxygen content causes vasodilatation of the lung vasculature, a drop in vascular resistance, closure of intracardiac and extracardiac shunting, and redirection of the ventricular output to the lungs. The partial pressure of oxygen rises to 70 to 80 mm Hg in the first 5 to 10 minutes after birth, and arterial Sp o 2 , reflecting the percentage of hemoglobin that is saturated with oxygen, oscillates between 95% and 100% once fetal-to-neonatal transition is completed.
Evolving Arterial Oxygen Saturation in the First Minutes After Birth
Dawson et al. merged databases from three research groups that included term and preterm newborn infants who did not need resuscitation or oxygen supplementation on stabilization ( Fig. 10.1 ). With these data, they assembled a graph of Sp o 2 ranges with centiles for term and late preterm babies for the first 10 minutes after birth. Reference ranges for term infants have been adopted by international guidelines to establish target Sp o 2 recommendations minute by minute. Thus recommended ranges for Sp o 2 are 60% to 65% at 1 minute, 65% to 70% at 2 minutes, 70% to 75% at 3 minutes, 75% to 80% at 4 minutes, 80% to 85% at 5 minutes, and 85% to 95% at 10 minutes. However, the reference ranges for preterm infants were based on a smaller population of 136 late preterm infants (33 6/7–36 6/7 weeks’ gestation). The percentiles for preterm infants did not reflect the evolving Sp o 2 in the first minutes after birth in very preterm infants ≤32 weeks’ GA. Vento et al. retrieved the Sp o 2 and heart rate (HR) minute by minute in very preterm infants ventilated with positive pressure and air, mimicking the real clinical situation in the DR. As shown in their nomogram, the results of the study by Vento et al. showed that very preterm infants on mask ventilation achieved higher Sp o 2 values and stabilized significantly earlier than did preterm infants.
Delaying cord clamping has been recommended by international guidelines in the past decade and is widely accepted as a routine intervention in the DR. , , Delaying cord clamping contributes to the hemodynamic stabilization of the newborn infant by increasing the left ventricular preload and afterload, decreasing pulmonary vascular resistance, and facilitating pulmonary gas exchange. Hence aerating the lungs and increasing pulmonary blood flow before umbilical cord clamping could avoid the reduction of cardiac preload and output caused by immediate cord clamping. Based on these assumptions, several clinical studies have reported the feasibility of ventilating newborn infants with patent cord, although no improvement in outcomes has been yet reported.
Recently, reference ranges for term infants born by vaginal delivery with cord patency delayed for more than 1 minute and no need for resuscitation or oxygen at birth have been constructed. Minute-by-minute data for HR and Sp o 2 were registered during the first 10 minutes after fetal expulsion. Significantly higher values for Sp o 2 for the 10th, 50th, and 90th centiles, compared with the reference range of Dawson et al. for the first 5 minutes, and for HR for the first 1 to 2 minutes after birth were reported. Hence in healthy infants newly born by vaginal delivery and with cord clamping delayed for >60 seconds, a higher Sp o 2 value and HR were achieved in the first 5 minutes after birth compared with term neonates born but with immediate cord clamping.
Initial Fi o 2 for Resuscitation in the Delivery Room
International guidelines established in 2015 , , strongly recommend initiating resuscitation of preterm infants born at <32 weeks’ GA who have a low oxygen concentration (21%–30%; Fig. 10.2 ), although the evidence that supports this recommendation is of moderate quality. The recent 2019 European Consensus Guidelines on the Management of Respiratory Distress Syndrome advocate the use of an Fi o 2 of 0.21 to 0.30 as the initial gas admixture for preterm infants <28 weeks’ gestation and 0.30 for babies 28 to 31 weeks’ gestation. Oei et al. launched an international survey that showed that the majority (77%) of neonatologists targeted Sp o 2 between the 10th and 50th percentiles of the reference range by Dawson et al. for full-term infants and would start with an Fi o 2 of 0.3. Interestingly, most participants acknowledged a lack of sufficient evidence and recommended further research. It could be hypothesized that the use of a lower initial Fi o 2 would reduce the oxygen load and the oxidative stress on stabilization. Oxidative stress has been linked as a causative agent to a series of neonatal conditions including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and IVH, among others. , In two randomized controlled trials (RCTs), the initiation of resuscitation with a high initial Fi o 2 (0.9 or 1.0) with subsequent titration resulted in increased oxidant stress and BPD incidence compared with starting with an Fi o 2 of 0.21 or 0.30. , In contrast, when the difference between higher (≥0.60) and lower (≤0.30) initial Fi o 2 was reduced, no differences in clinical outcomes or biomarkers of oxidative stress were found in two RCTs blinded for the air/oxygen blender. , In contrast, a nonblinded RCT performed in extremely premature infants (<28 weeks’ gestation) raised concerns about the optimal strategy to supplement oxygen to extremely preterm infants. The TO2RPIDO study randomized infants <32 weeks’ GA to air or 100% oxygen. The Sp o 2 was targeted to 65% to 95% at 5 minutes and 85% to 95% at NICU admission. A total of 287 infants with a mean GA of 28.9 weeks were included. In a nonprespecified post hoc analysis, infants <28 weeks’ GA had an almost four-fold increase in mortality if initially started with air compared with 100% oxygen (risk ratio, 3.9; 95% CI, 1.1–13.4). It should be underpinned that this study was underpowered to address this post hoc hypothesis reliably, and the trial was ceased per recommendation of the data and safety monitoring committee due to loss of equipoise for the use of 100% oxygen. Furthermore, Oei et al. performed a systematic review of the outcomes of infants born at ≤28 6/7 weeks’ gestation randomized to resuscitation with a low (≤0.3) versus high (≥0.6) Fi o 2 at delivery in eight RCTs that fulfilled these requirements. They did not find differences in the overall risk of death or other common preterm morbidities including BPD, NEC, ROP, PDA, or IVH after resuscitation was initiated at delivery in infants with lower versus higher Fi o 2 . Additional evidence has been reported in two major systematic reviews and meta-analyses. Lui et al. performed a Cochrane systematic review of 10 RCTs that included 914 infants. No significant impact was assessed on death at discharge or relevant neonatal conditions such as ROP, periventricular leukomalacia, IVH, NEC, BPD, PDA, or neurodevelopmental outcome in preterm infants born at ≤32 weeks’ gestation with a lower (<0.4) or higher (≥0.4) initial Fi o 2 titrated to target Sp o 2 . Almost simultaneously, Welsford et al., in a systematic review and meta-analysis that included 10 RCTs and 4 cohort studies with a total of 5697 preterm infants born at <35 weeks’ gestation, compared a higher (>50%) versus lower (<50%) initial Fi o 2 for outcomes of resuscitation in the DR. This study also failed to show differences in short-term mortality, long-term mortality, neurodevelopmental impairment, or other relevant preterm morbidities in the neonatal period. However, the authors pointed out that most of the subgroup of newborns of ≤32 weeks’ gestation required oxygen supplementation on stabilization.
