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Journal of Pediatric Biochemistry 3 (2013) 155–159 DOI 10.3233/JPB-130088 IOS Press
Review Article
Oxygen for the resuscitation of newborn infants a
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Elena Cubellsa, María Cernadaa, Isabel Torres-Cuevasa, Julia Kuligowskia, Javier Escobara, Marta Aguarb, Raquel Escrigb and Máximo Ventoa,b,* Division of Neonatology, University and Polytechnic Hospital La Fe, Valencia, Spain Neonatal Research Group, Health Research Institute La Fe, Valencia, Spain
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Received 1 January 2013 Revised 1 April 2013 Accepted 11 May 2013
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Abstract. Fetal to neonatal transition is characterized by abrupt changes in the cardio-respiratory physiology. In few minutes, the newly born infant expands the lungs, diminishes pulmonary vascular resistance dilating the pulmonary vessels, and establishes a highly efficient gas exchange between alveoli and the pulmonary capillary bed. However, under certain pathologic conditions asphyxia ensues. Asphyxia is characterized by prolonged periods of hypoxia and ischemia that cause brain energy exhaustion leading in many occasions to a hypoxic ischemic encephalopathy. The cornerstones of newborn resuscitation consist in the establishment of a functional residual capacity and an adequate oxygenation. Of note, the need for oxygen during resuscitation varies substantially between term and preterm infants as has been shown in physiologic studies. The aim of this review article is to present updated knowledge in the management of oxygen in the delivery room both in term babies suffering from birth asphyxia and in preterm babies needing aid to overcome postnatal adaptation. Keywords: Oxygen, fetal-to-neonatal transition, resuscitation, oxidative stress, pulse oximetry
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1. Introduction
World-wide, between 0.5–3% of newborn infants suffers birth asphyxia requiring resuscitation. Out of these, approximately 1 million will die and a similar number of infants will develop motor and/or neurocognitive dysfunctions. Resuscitation of the newborn is considered the most frequent and one of the most stressful interventions in the neonatal period. In order to perform a successful resuscitation, both birth attendants have to be adequately trained and the equipment has to meet to standards required by the International Resuscitation Guidelines [1]. In 2010 the ___________________________________________ *Corresponding author: Máximo Vento, Division of Neonatology, University and Polytechnic Hospital La Fe Bulevar Sur s/n, 46026 Valencia, Spain. Tel.: +34 96 1245688; Fax: +34 96 1244657; E-mail:
[email protected].
new guidelines for newborn resuscitation by the International Liaison Committee on Resuscitation (ILCOR) were released and for the first time relevant changes in the management of oxygen during resuscitation were addressed [2]. Notwithstanding, there is still a big gap of knowledge in the precise management of oxygen in the delivery room, and especially in preterm infants. The present review aims to at least partially fill this gap with the most recent contributions in the scientific literature.
2. Physiologic changes in oxygenation in the fetal to neonatal transition. Fetal to neonatal transition represents an enormous metabolic challenge for the human fetus. Late in
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50% to > 90%, while in preterm infants time to achieving an SpO2 plateau ~ 90% was found to be around 10–15 min [14]. SpO2 readings from a cohort of 468 infants (25–42 weeks’ gestation) who did not receive oxygen or other interventions in the delivery room were used to construct charts illustrating the 10th to 90th percentiles which reflect saturation values minute to minute for the first 10 minutes after birth [15]. The percentile lines represent the proportion of infants with SpO2 values below each percentile at each time point (Fig. 1). The graph shows that healthy newly born infants have an ample range of saturation values [15]. 3.2. Measuring saturation in the delivery room
Measurement of arterial oxygen saturation has undoubtedly substituted clinical judgment based on the infant’s color. Hence, measurement of oxygen saturation as measured by pulse oximetry is at present the most recommended means of monitoring arterial oxygen saturation during resuscitation in the delivery room. Remarkably, it provides a continuous display of oxygen saturation and heart rate and how these change. Achievement of reliable measurements is very rapid especially when connected to the right hand which corresponds to pre-ductal values and in expert hands it will take only 60–90 seconds. Last generation pulse oximeters are able to detect hypoxia although the range of variability below 70% SpO2 may depend on the type of monitor, gestational age, type of sensor and adjustments of frequency of signaling and sensitivity. However, persistent low values should be confirmed with arterial blood gas analysis. In addition, it should be underscored that SpO2 values above 95% may correspond to partial pressures of oxygen in arterial blood well above physiologic values [16].
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gestation high pulmonary vascular resistance of the human fetal pulmonary circulation is will condition a low blood flow to the lung. As a consequence, a major fraction of the cardiac output is diverted away from the lung to other organs via the foramen ovale and the ductus arteriosus [3]. Remarkably, oxygen tension in the fetal pulmonary circulation is lower than in the newborn and the adult. However, in the first minutes after birth arterial partial pressure of oxygen (paO2) will raise from 3.1 kPa to 9.3 kPa and as a consequence oxygen delivery to tissue will drastically increase [4]. Sudden increase of oxygen availability by tissue will cause a burst of reactive oxygen species to occur especially in the mitochondrial respiratory chain and cause a physiologic oxidative stress [5]. Conspicuously, free radicals in the fetal-to-neonatal transition may act as signaling molecules modulating maturation of specific metabolic pathways [6,7]. However, level and activity of the most-relevant antioxidant enzymes such, as superoxide dismutases, catalase, and glutathione peroxidase change dynamically during development and only mature in the last weeks of gestation preparing the fetus for lung respiration [8–10]. Therefore, babies born prematurely are at high risk of developing oxidative stress associated conditions. Hence, immediately after birth it has been shown that increased production of free radicals especially anion superoxide may sequester endotheliumderived nitric oxide and predispose preterm infants to pulmonary vasoconstriction and pulmonary hypertension [11]. Furthermore, prematurity will also predispose to chronic conditions such as bronchopulmonary dysplasia, retinopathy of prematurity or intraperiventricular hemorrhage [12]. Interestingly, maturation is gender related and the use of antenatal steroids enhances antioxidant enzymes’ activation thus increasing postnatal adaptability of preterm infants [13].
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3. Oxygen supplementation in the delivery room 3.1. What is the normal range of oxygen saturation in the first minutes of life? Applying pulse oximeter in the right hand or wrist to a newly born infant will rapidly (within 90 seconds) provide values of pre-ductal arterial oxygen saturation (SpO2). In term infants, it has been shown that it takes around 5 minutes for preductal SpO2 to rise from ~
3.3. The use of oxygen in term infants In term infants, the ILCOR guidelines recommend the use of an initial inspiratory fraction of oxygen of 21% when supplemental oxygen with positive pressure ventilation in the delivery room is needed [2]. This is in accordance with the results of studies performed by Ramji and colleagues [17,18], Saugstad and colleagues [19] and Vento and colleagues [20–22] and others that were summarized in a recent metaanalysis [23] which showed that the use of room air as initial gas admixture for the resuscitation of depressed
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Fig. 1. Arterial oxygen saturation as measured by pulseoximetry in newly born infants. The graph depicts arterial oxygen saturation as measured by pulse oximetry (SpO2) in the first 10 minutes after birth. Data comprising 10% to 90% centiles have been represented as grey bars at each minute, and median has been represented as a white transversal line within each bar. Data have been retrieved from Dawson and colleagues [15].
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newly born infants significantly reduced the mortality both in the analysis of all studies (typical RR 0.69, 95% CI 0.54, 0.88) and in the analysis of strictly randomized studies (typical RR 0.32, 95% CI 0.12, 0.84). In asphyctic term babies an adequate ventilatory support should be established and FiO2 titrated according to the SpO2 readings as recommended by ILCOR 2010 [2]. Special emphasis should be paid to the heart rate which is the most reliable clinical reference guiding resuscitation in the delivery room [1, 2]. Importantly, in babies with sentinel events indicating intrauterine hypoxia and/or neurological signs revealing asphyxia evolving towards hypoxic-ischemic encephalopathy the radiant heater should be switched of and resuscitation should be performed allowing the baby to reach spontaneous hypothermia (33.5–34ºC) [1]. 3.4. The use of oxygen in preterm infants Preterm infants and especially very preterm below 32 weeks gestation delay or even not initiate the establishment of an active and effective respiratory effort immediately after birth in the delivery room. Accordingly, they will need respiratory support and oxygen supplementation. The recommendation of the ILCOR regarding the use of oxygen in preterm infants
is quite vague and unspecific. ILCOR recommends using blended air and oxygen according to the infant’s needs guided by pulse oximetry trying to avoid hyperand/or-hypoxia [2]. The European Consensus Guidelines recommend low initial FiO2 have made similar recommendations. What should be the initial FiO2 employed in preterm infants? Of note, most preterm infants are not born after a severe asphyctic insult, and many of them will just need a mild support to establish an adequate pattern of respiration and adequate SpO2 [24]. However, respiratory support will require the use of air/oxygen admixtures to achieved established saturation targets [15]. The conundrum regarding the use of oxygen in preterm infants is still going on. On one side, recent multicenter randomized controlled trials (SUPPORT TRIAL; BOOST II TRIAL) have shown that preterm infants kept within lower margins of SpO2 in the neonatal intensive care unit had a lower incidence of retinopathy of prematurity but higher mortality [25,26]. Contrarily, accepted normality ranges of saturation in the delivery room are quite low initially and should not be reaching values around 90% until 10– 15 minutes after birth have elapsed [14]. This affirmation is based on the risk of causing increased oxidative stress and damage in babies with lower antioxidant capacity. Hence, Vento and colleagues [27] showed increased biomarkers of oxidative stress es-
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Acknowledgements This study was funded with a FIS grant PI011/0313 to M Vento, J Escobar, E Cubells and M Aguar, CD12/00667 grant to J Kuligowski, FI12/00109 grant to I Torres-Cuevas from the Instituto Carlos III (Ministry of Economy and Competitiveness; Spain) and Health Research Institute Research Grant to M Cernada.
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Conflict of interest
None of the authors declares having conflicts of interest.
References
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pecially caused by hyperoxia such as isofurans, and an increased rate of bronchopulmonary dysplasia in preterm infants initially resuscitated with an initial FiO2 of 90% as compared to those resuscitated with initially with FiO2 of 30%. In order to clarify our present state of knowledge a recent systematic appraisal and review of randomized controlled trials has been performed [28]. A total of six randomized controlled trials were analyzed comprising 484 infants. Most of these infants were below 32 weeks gestation. Meta-analyses found a statistically significant reduction in the risk of death pooled risk ratio 0.65 (95% confidence interval 0.43, 0.98). However, this effect disappeared when only the four trials with adequate allocation concealment were included [pooled risk ratio 1.0 (95% confidence interval 0.45, 2.24). The authors conclude that with the available data there is not sufficient evidence to affirm that the use of lower or higher initial FiO2 in the delivery room for preterm babies confers important benefits or harms [28]. However, after this study was published new information has been substantiated that has not been yet analyzed but that may permit reaching sufficient evidence to establish new guidelines for the use of oxygen in the delivery room [29–32]. In conclusion, until we have this new evidence, we recommend the use of an initial FiO2 between 21% and 30% in all preterm infants. Every preterm baby should have a pulse oximeter adjusted to the right hand to measure pre-ductal pulse oximetry. With an adequate training reliable measurement can be achieved within one to two minutes. FiO2 should be titrated according to the SpO2 readings with changes performed ever 30 seconds to allow babies cardiorespiratory response. Strict control of heart rate is essential because heart rate is extremely sensitive to hypoxia, and bradycardia is the most reliable parameter indicating that the baby needs either better ventilation or more oxygen. In this regard, it should be remembered that the corner stone of resuscitation is the achievement of a functional residual capacity and the establishment of adequate alveolar ventilation. If the baby is not adequately ventilated because of mask leakage, insufficient tidal volume, or flow volume increasing oxygen concentration will not solve the problem. However, if the baby is adequately ventilated FiO2 should be titrated according to the readings of the pulse oximeter and kept within the recommended range of Dawson’s nomogram [15].
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