Optimizing Oxygenation of the Extremely Premature Infant during the First Few Minutes of Life: Start Low or High?
2020; Elsevier BV; Volume: 227; Linguagem: Inglês
10.1016/j.jpeds.2020.07.034
ISSN1097-6833
AutoresOla Didrik Saugstad, Satyan Lakshminrusimha, Máximo Vento,
Tópico(s)Respiratory Support and Mechanisms
ResumoOne of the burning questions in contemporary neonatology is how to oxygenate preterm infants, especially the extremely preterm ones (<30 weeks of gestational age at birth) and in the first minutes of life. For term and near-term infants in need of stabilization/resuscitation at birth, there is agreement to start with air and titrate the inspired fraction of oxygen (FiO2) according to the development of oxygen saturation (SpO2) compared with the Dawson reference range curves, with the aim of reaching an SpO2 of 80%-85%, corresponding to the 25th-50th percentiles of the Dawson reference range curves at 5 minutes of age.1Dawson J.A. Kamlin C.O. Vento M. Wong C. Cole T.J. Donath S.M. et al.Defining the reference range for oxygen saturation for infants after birth.Pediatrics. 2010; 125: e1340-e1347Crossref PubMed Scopus (323) Google Scholar,2Kattwinkel J. Perlman J.M. Aziz K. Colby C. Fairchild K. Gallagher J. et al.Part 15: Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.Circulation. 2010; 122: S909-S919Crossref PubMed Scopus (384) Google Scholar However, recent observations in extremely preterm infants have raised questions regarding optimal oxygenation of these infants. Ten years ago, randomized studies by Escrig et al3Escrig R. Arruza L. Izquierdo I. Villar G. Sáenz P. Gimeno A. et al.Achievement of targeted saturation values in extremely low gestational age neonates resuscitated with low or high oxygen concentrations: a prospective, randomized trial.Pediatrics. 2008; 121: 875-881Crossref PubMed Scopus (178) Google Scholar and Vento et al4Vento M. Moro M. Escrig R. Arruza L. Villar G. Izquierdo I. et al.Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.Pediatrics. 2009; 124: e439-e449Crossref PubMed Scopus (328) Google Scholar showed that extremely preterm infants could be satisfactorily stabilized using 0.3 as the initial FiO2. No differences in SpO2 or heart rate were evident in the first 10 minutes when compared with infants initially stabilized with an FiO2 of 0.9. Concomitantly, Wang et al launched a study with preterm infants randomized to an FiO2 of 0.21 or 1.0 as needed in conjunction with artificial ventilation.5Wang C.L. Anderson C. Leone T.A. Rich W. Govindaswami B. Finer N.N. Resuscitation of preterm neonates by using room air or 100% oxygen.Pediatrics. 2008; 121: 1083-1089Crossref PubMed Scopus (195) Google Scholar Infants who initially received room air had prolonged bradycardia and lower SpO2 in the first 3-5 minutes after birth, and a significant number were switched to pure oxygen. Recently, the TORPIDO study randomized infants <32 weeks of gestational age to air or 100% O2.6Oei J.L. Saugstad O.D. Lui K. Wright I.M. Smyth J.P. Craven P. et al.Targeted oxygen in the resuscitation of preterm infants, a randomized clinical trial.Pediatrics. 2017; 139: e20161452Crossref PubMed Scopus (58) Google Scholar For the entire study cohort, there was no difference in morbidity or mortality between the 2 groups; however, in a post hoc analysis, infants <28 weeks of gestational age had an almost 4-fold increased risk for mortality if initially started with air compared with 100% O2 (relative risk, 3.9; 95% CI, 1.1-13.4).6Oei J.L. Saugstad O.D. Lui K. Wright I.M. Smyth J.P. Craven P. et al.Targeted oxygen in the resuscitation of preterm infants, a randomized clinical trial.Pediatrics. 2017; 139: e20161452Crossref PubMed Scopus (58) Google Scholar In sharp contrast, in 2 blinded randomized trials comparing an initial FiO2 of 0.3 vs 0.60 or 0.65, a tendency toward an increased survival rate was found in the group with the lower initial FiO2.4Vento M. Moro M. Escrig R. Arruza L. Villar G. Izquierdo I. et al.Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.Pediatrics. 2009; 124: e439-e449Crossref PubMed Scopus (328) Google Scholar,7Rook D. Schierbeek H. Vento M. Vlaardingerbroek H. van der Eijk A.C. Longini M. et al.Resuscitation of preterm infants with different inspired oxygen fractions.J Pediatr. 2014; 164: 1322-1326.e3Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Further studies have shown that preterm infants 80% and heart rate of >100 bpm by 5 minutes; and (6) avoid oxidative stress–induced injury. Dekker et al randomized preterm infants <30 weeks of gestation to be stabilized at birth with either 30% or 100% oxygen (Figure 2) based on the Dawson curves.1Dawson J.A. Kamlin C.O. Vento M. Wong C. Cole T.J. Donath S.M. et al.Defining the reference range for oxygen saturation for infants after birth.Pediatrics. 2010; 125: e1340-e1347Crossref PubMed Scopus (323) Google Scholar,12Dekker J. Martherus T. Lopriore E. Giera M. McGillick E.V. Hutten J. et al.The effect of initial high vs. low FiO2 on breathing effort in preterm infants at birth: a randomized controlled trial.Front Pediatr. 2019; 7: 504Crossref PubMed Scopus (13) Google Scholar When the initial FiO2 setting was 0.3 and the SpO2 was below the 25th percentile, the FiO2 was titrated up to 0.5 and subsequently to 1.0. If the SpO2 exceeded 90% with this initial setting, the FiO2 was titrated down to 0.21 directly. When the initial FiO2 setting was 1.0 and the SpO2 exceeded 90%, the FiO2 was titrated down to 0.5 and subsequently to 0.3 and 0.21. SpO2 values were monitored continuously, and when values were outside the range, FiO2 was titrated every 30 seconds. Cord clamping was performed after 30 seconds in infants with apnea and after 60 seconds in breathing infants. Respiratory support was provided using a T-piece resuscitator (Neopuff; Fisher & Paykel Healthcare, Auckland, New Zealand). Out of 109 eligible infants, 26 infants were randomized to the 30% O2 group and 24 were randomized to the 100% O2 group. Six infants were excluded from the analysis owing to a lack of physiological measurements, leaving 44 infants for analysis. The mean birth weight was 931 ± 256 g in the 30% O2 group and 992 ± 309 g in the 100% O2 group. Only 52% of the infants in both groups received a full course of antenatal steroids. The primary outcome of average minute volume in the first 5 minutes after birth was significantly higher in the 100% O2 group compared with the 30% O2 group (mean, 146.34 ± 112.68 mL/kg/minute vs 74.43 ± 52.19 mL/kg/min; P = .014). Average tidal volume was also significantly higher in the 100% O2 group (4.8 ± 3.8 mL/kg vs 3.8 ± 3.7 mL/kg; P = .006), and the median duration of mask ventilation in the first 10 minutes after birth was shorter (23.6 seconds [range, 0-122.2 seconds] vs 108.3 seconds [range, 46.4-205.1 seconds]; P = .021). Median SpO2 in the first 5 minutes after birth was significantly higher in the 100% O2 group (85% [range, 64%-93%] vs 58% [range, 46%-67%]; P < .001). In the first 5 minutes, infants in the 100% O2 group had a significantly higher percentage of SpO2 between 90% and 95%, whereas at 5-10 minutes after birth, there was no significant difference between the groups. An SpO2 of 80% was reached more than 1 minute earlier in the 100% O2 group (mean, 178 ± 70 seconds vs 261 ± 80 seconds after birth) and less time was spent with an SpO2 <25th percentile of the reference ranges described by Dawson et al (median, 73 seconds [range, 0-189 seconds] vs 158 seconds [range, 116-184 seconds]; P = .018).1Dawson J.A. Kamlin C.O. Vento M. Wong C. Cole T.J. Donath S.M. et al.Defining the reference range for oxygen saturation for infants after birth.Pediatrics. 2010; 125: e1340-e1347Crossref PubMed Scopus (323) Google Scholar Dekker et al report that initiating ventilation with 100% O2 followed by careful oxygen titration led to a shorter period of hypoxemia without a longer duration of hyperoxemia. Importantly, the total oxygen load (described as the area under the curve for FiO2) was not significantly different between the groups, and oxidative stress, as assessed by the level of 8-iso-prostaglandin F2α in cord blood and in blood at 1 and 24 hours of age, did not differ between the groups (Figure 2). Even though the number of patients was small, the rates of intubation (only 2 infants in the 30% oxygen group needed intubation in the delivery room), intraventricular hemorrhage grade ≥III, or death before hospital discharge did not significantly differ between the 2 groups.12Dekker J. Martherus T. Lopriore E. Giera M. McGillick E.V. Hutten J. et al.The effect of initial high vs. low FiO2 on breathing effort in preterm infants at birth: a randomized controlled trial.Front Pediatr. 2019; 7: 504Crossref PubMed Scopus (13) Google Scholar Based on these data, Dekker et al suggest "that oxygenation might be an important determinant in stimulating breathing and decreasing the need for positive-pressure ventilation," and argue that it is best to start with a brief pulse of high oxygen and titrate down, with the goal of avoiding any hypoxemia in the first minutes after birth. They also state that hyperoxia should be avoided during resuscitation of extremely preterm infants.12Dekker J. Martherus T. Lopriore E. Giera M. McGillick E.V. Hutten J. et al.The effect of initial high vs. low FiO2 on breathing effort in preterm infants at birth: a randomized controlled trial.Front Pediatr. 2019; 7: 504Crossref PubMed Scopus (13) Google Scholar We agree with Dekker et al that we currently do not know the optimal initial FiO2 for immature infants, but we question whether this means that an FiO2 of 1.0 should always be used instead of the recommended 0.3, and we believe that the data are insufficient to support such a conclusion. The study included a small population of selected infants, did not report separate data for those infants born at 24-26 weeks of gestation vs 27-29 weeks as stratified during allocation, and did not include neurodevelopmental outcomes. We believe there are several arguments against beginning resuscitation with an FiO2 of 1.0 and titrating down according to the Dawson SpO2 curves. First, we do not know the optimal evolution of SpO2 during the first few minutes after birth in extremely preterm infants. The Dawson curves are based mostly on term infants. We do not know whether the 25th percentile of Dawson curves represents a cutoff of hypoxemia in extremely preterm infants with respiratory depression or in spontaneously breathing preterm infants. Dekker et al argue that the total amount of oxygen exposure may even be less if resuscitation is initiated with higher FiO2. Although this might be true, we do not know which is more detrimental—the total amount of oxygen exposure or the peak oxygen concentration.4Vento M. Moro M. Escrig R. Arruza L. Villar G. Izquierdo I. et al.Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.Pediatrics. 2009; 124: e439-e449Crossref PubMed Scopus (328) Google Scholar Dekker et al measured oxidative stress only for the first 24 hours; however, even a brief (minutes) hyperoxic exposure immediately after birth has been shown to trigger increased oxidative and inflammatory stress for at least several weeks.4Vento M. Moro M. Escrig R. Arruza L. Villar G. Izquierdo I. et al.Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease.Pediatrics. 2009; 124: e439-e449Crossref PubMed Scopus (328) Google Scholar In newborn hypoxic piglets, 30 minutes of exposure to 100% O2 compared with 21% O2 resulted in increased oxidative biomarkers of damage to proteins and DNA, peroxynitrite, fragmentation of hyaluronic acid, inflammation, and tumor necrosis factor-α and interleukin-1β expression in the lung.13Østerholt H.C. Dannevig I. Wyckoff M.H. Liao J. Akgul Y. Ramgopal M. et al.Antioxidant protects against increases in low molecular weight hyaluronan and inflammation in asphyxiated newborn pigs resuscitated with 100% oxygen.PLoS One. 2012; 7e38839Crossref PubMed Scopus (23) Google Scholar It is known that hyperoxia may induce damage to cellular structures, impairment of oxidative phosphorylation and thus also of adenosine triphosphate production, increased inflammation and apoptosis for days or weeks, down-regulation of DNA protection and repair, and alterations in cell growth.14Saugstad O.D. Oei J.L. Lakshminrusimha S. Vento M. Oxygen therapy of the newborn from molecular understanding to clinical practice.Pediatr Res. 2019; 85: 20-29Crossref PubMed Scopus (25) Google Scholar, 15Solberg R. Enot D. Deigner H.P. Koal T. Scholl-Bürgi S. Saugstad O.D. et al.Metabolomic analyses of plasma reveals new insights into asphyxia and resuscitation in pigs.PLoS One. 2010; 5: e9606Crossref PubMed Scopus (90) Google Scholar, 16Wollen E.J. Sejersted Y. Wright M.S. Bik-Multanowski M. Madetko-Talowska A. Günther C.C. et al.Transcriptome profiling of the newborn mouse lung after hypoxia and reoxygenation: hyperoxic reoxygenation affects mTOR signaling pathway, DNA repair, and JNK-pathway regulation.Pediatr Res. 2013; 74 ([erratum 2014;76:323]): 536-544Crossref PubMed Scopus (18) Google Scholar, 17Wollen E.J. Sejersted Y. Wright M.S. Madetko-Talowska A. Bik-Multanowski M. Kwinta P. et al.Transcriptome profiling of the newborn mouse brain after hypoxia-reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes.Pediatr Res. 2014; 75: 517-526Crossref PubMed Scopus (16) Google Scholar, 18Rognlien A.G. Wollen E.J. Atneosen-Åsegg M. Saugstad O.D. Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation.Pediatr Res. 2015; 77: 326-333Crossref PubMed Scopus (16) Google Scholar Moreover, from a practical standpoint, titration in the delivery room is difficult, especially in emergency situations, and achievement of the desired FiO2 can be significantly delayed compared with titration in a strictly controlled research setting.9Binder-Heschl C. Pichler G. Avian A. Schwaberger B. Baik-Schneditz N. Mileder L. et al.Oxygen saturation targeting during delivery room stabilization: what does this mean for regional cerebral oxygenation?.Front Pediatr. 2019; 7: 274Crossref PubMed Scopus (7) Google Scholar,19Dekker J. Stenning F.J. Willms L.J.F.B. Martherus T. Hooper S.B. Te Pas A.B. Time to achieve desired fraction of inspired oxygen using a T-piece ventilator during resuscitation of preterm infants at birth.Resuscitation. 2019; 136: 100-104Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Thus, preterm infants started with a high FiO2 would be at risk of receiving a higher oxygen load for a longer than desirable period. So, which factors are most important, and how do we find a balance between these arguments? At a minimum, we need large randomized studies of contemporary populations of immature newborn infants. Several developments in the last decade have added complexity to the interpretation of previous randomized studies evaluating optimal oxygenation in preterm infants. Routine resuscitation of extremely preterm infants <24 weeks of gestational age, delayed cord clamping, and ventilation with an intact cord emphasize the need for new randomized trials evaluating initial oxygen concentration in extremely preterm infants. In addition, there is a need to precisely compare a wider range of initial FiO2 settings at 0.21, 0.30, 0.40, and perhaps 0.60 to define the optimal initial FiO2 in infants <32 weeks of gestational age. We need to determine the optimal development of SpO2 over the first minutes after birth for very preterm infants and identify how to titrate oxygen to reach this target. Until such data are available, we do not recommend starting with an FiO2 of 1.0 and titrating down, especially because the potential long-term adverse effects of such a practice are presently unknown. From the experience gathered with more than 500 infants monitored minute by minute in the first 10 minutes after birth, infants 80% and a heart rate >100 bpm within 5 minutes (Figure 3).20Sweet D.G. Carnielli V. Greisen G. Hallman M. Ozek E. Te Pas A. et al.European consensus guidelines on the management of respiratory distress syndrome - 2019 update.Neonatology. 2019; 115: 432-450Crossref PubMed Scopus (278) Google Scholar The aggressiveness of oxygen titration also may be influenced by the presence of bradycardia and the trend in heart rate. A steadily increasing heart rate >100 bpm may warrant a less dramatic titration of FiO2, especially if the SpO2 is close (within 5%) of the target range. We acknowledge that our recommendations are also not completely supported by current evidence. More multicenter, randomized trials evaluating initial FiO2, optimal SpO2 targets, and the magnitude and frequency of FiO2 titration during resuscitation of extremely preterm infants are warranted, and these should include long-term outcomes. Except for these situations in extremely preterm infants, we suggest following international guidelines recommending an initial FiO2 of 0.21-0.30 for infants 28-31 weeks of gestational age, with the use of pulse oximetry to guide subsequent FiO2 adjustments up or down. For infants 100 bpm should be achieved within 5 minutes.20Sweet D.G. Carnielli V. Greisen G. Hallman M. Ozek E. Te Pas A. et al.European consensus guidelines on the management of respiratory distress syndrome - 2019 update.Neonatology. 2019; 115: 432-450Crossref PubMed Scopus (278) Google Scholar Optimizing oxygenation of the preterm infant directly at birth: focus of future studiesThe Journal of PediatricsVol. 229PreviewThe optimal oxygen concentration during stabilization of extremely preterm infants at birth was recently discussed by Saugstad et al.1 The authors comment on the findings of our randomized clinical trial, which compared commencing stabilization of extremely preterm infants with 100% vs 30% O2.2 With careful titration, commencing with 100% O2 increased respiratory effort and did not increase the risk of hyperoxia.2 Saugstad et al question the implication of these findings and recommend against initiating stabilization with 100% O2. Full-Text PDF
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