Why Are We Still Using Oxygen to Resuscitate Term Infants?

OD Saugstad Department of Pediatric Research, Oslo University Hospital, University of Oslo, Oslo, Norway

infants.1 The Apgar score with the inclusion of skin color also This article summarizes the historical background for the use of oxygen contributed to an increased use of oxygen. In 1966, Klaus and during newborn resuscitation and describes some of the research and the Meyer wrote: ‘there is no contraindication to the use of warm 100% process of changing the previous practice from a high- to a low-oxygen oxygen during resuscitation. The birth process is an asphyxia approach. Findings of a recent Cochrane review suggest that more than episode, and high concentrations of oxygen during the first 100 000 newborn lives might be saved globally each year by changing from minutes of life can only be helpful.’2 100 to 21% oxygen for newborn resuscitation. This estimate represents one It is surprising how earlier generations introduced this therapy of the largest yields for a simple therapeutic approach to decrease neonatal and how one generation followed the next without asking critical mortality in the history of pediatric research. Available data also suggest questions about its validity. It is interesting, perhaps even shocking, that, for the very low birth weight infant, use of the low-oxygen approach to realize that oxygen therapy was introduced without any scientific should be considered with the understanding that some of the smallest and evidence. It is even more surprising that only few questioned this sickest preterm neonates will need some level of oxygen supplementation routine during the ensuing years. The 1992 International Liaison during the first minutes of postnatal life. As more data are needed for the Committee on Resuscitation (ILCOR) guidelines for newborn very preterm population, creation of strict guidelines for these infants would resuscitation stated that ‘oxygen should be used, it is not toxic be premature at present. However, it can be stated that term and late and there is no reason to be concerned.’3 However, in 1966 preterm infants in need of resuscitation should, in general, be started on Campbell et al.4 had already shown in newborn rabbits that 21% oxygen, and if resuscitation is not started with 21% oxygen, a blender it is possible to resuscitate with room air. should be available, enabling the administration of the lowest FiO2 possible I became concerned about the potential harm of using 100% 5 to keep heart rate and SaO2 within the target range. For extremely low birth oxygen in resuscitation and raised this issue in 1980. On the basis weight infants, initial FiO2 could be between 0.21 and 0.30 and adjusted of our studies showing that the purine metabolite, hypoxanthine, according to the response in SaO2 and heart rate. accumulates during hypoxia, we and others understood that Journal of Perinatology (2010) 30, S46–S50; doi:10.1038/jp.2010.94 introducing oxygen in the aftermath of hypoxia could lead to 5,6 Keywords: newborn resuscitation; 21% oxygen; 100% oxygen; oxygen an explosive generation of oxygen-free radicals. These studies toxicity represent the basis for understanding the hypoxia–reoxygenation or ischemia-reperfusion injury that has puzzled medicine far beyond neonatology. This point is clearly illustrated in a recent study in asphyxiated term newborn lambs, in which resuscitation Background with 21%, 100% for 3 min or 100% for 30 min showed a very high subcortical pO when oxygen supplementation was used The history of the use of oxygen in newborn resuscitation has been 2 (Figure 1).7 Indeed, if oxygen had been considered as a drug, recently summarized by Obladen.1 Briefly, oxygen was introduced many of the pitfalls by the liberal use of oxygen could have in newborn care more than 200 years ago. In 1777, Dr Chaussier been avoided. developed a device for the use of oxygen in neonatal resuscitation and made oxygen the first drug to be used specifically in neonates. Within a few years, oxygen was widely used in neonatal resuscitation throughout Europe and it was even injected Discovery through a failure intravenously into the umbilical vein of asphyxiated newborn In 1980, I stated that oxygen supplementation should be reduced during resuscitation in both adults and newborn infants, but I did Correspondence: Dr OD Saugstad, Department of Pediatric Research, Rikshospitalet, Rikshospitalet Medical Center, Sognsvannsvn 20, Oslo 0027, Norway. not investigate this issue further at that time. Instead, I focused E-mail: [email protected] on how oxygen radicals could injure premature infants, creating 8 This paper resulted from the Evidence vs Experience in Neonatal Practices conference, what I called ‘The oxygen radical disease of neonatology’. 19 to 20 June 2009, sponsored by Dey, LP. However, at the end of the 1980s, one of my PhD fellows performed Oxygen to resuscitate term infants OD Saugstad S47

PaO2 in the brain - newborn lambs Subsequent experimental studies and clinical studies by Max Vento and his group and others have been extremely important, as these 400 studies presented evidence that it is actually harmful to resuscitate newborn babies with 100% oxygen.20–26 300 The Resair 2 study was criticized mainly for two reasons. First, the study was not strictly randomized nor was it blinded. Second, 200

mm Hg most of the babies were enrolled in low income countries and even 100 the ethics of conducting such a study were questioned by some. In contrast, it is interesting that no one had ever objected to the use of 0 pure oxygen for newborn resuscitation, a drug that had never been 21% 30' 100% 3' 100% 30' 21% 27' tested in a randomized controlled study. As late as 2000, as information on the potential benefits of the new low-oxygen Figure 1 Asphyxia was induced in newborn lambs by a 10-min clamping of approach was spreading, it was still stated by one author: ‘Oxygen cord. The animals were then resuscitated with 21% O2 for 30 min, 100% O2 for 3 min and then 21% for 27 min, or 100% O2 30 min (adapted from should be used as soon as possible, in as near 100% as possible Perez-de-Sav et al.7). in all resuscitation situations, and for the early management of injury and illness. Its use will never disadvantage a patient under these circumstances’.27 I believe this is a lesson teaching us to be some experiments to study necrotizing enterocolitis in rat intestine, always cautious about our conclusions, especially as now we which turned out to be a failure. To help him out, I suggested at understand that using 100% oxygen gives reason for concern. that time to test instead the use of room air in resuscitation in a newborn piglet model we had developed. His results showed for the first time that it is possible indeed to resuscitate with 21%.9 Another A slow change in attitudes PhD fellow, Terje Rootwelt, continued the study by first developing The ILCOR guidelines of 1992 had absolutely no reservation in a refined newborn model. In this and a series of subsequent using pure oxygen for newborn resuscitation.3 The guidelines of experiments, we confirmed that 21% oxygen is as efficient as 1999 somewhat modified this view.28 I had the privilege to take 100% oxygen for resuscitation.10–16 part in the preparation of these guidelines and agreed to myself The findings in the newborn piglet were consistent, and that there was not sufficient data to change the practice at that I realized that the time had come to test our hypothesis in a time. It was, however, an important signal from ILCOR and clinical study. Siddarth Ramji in New Delhi immediately agreed to from the American Academy of Pediatrics when it was stated that, participate, and the pilot clinical trial was carried out in India, if oxygen is not available, ambient air should be used. Nevertheless enrolling 84 newborn infants randomized to room air or 100% the 1999/2000 guidelines remained quite conservative and oxygen resuscitation. We found that babies resuscitated in room cautious, whereas in 1998, the World Health Organization stated air recovered as quickly as those who received 100% oxygen.17 that room air should be the first choice for basic newborn I assumed that this study would trigger hectic research activity resuscitation.29 by other groups, but not much happened. I realized, therefore, that The next set of ILCOR/American Academy of Pediatrics a larger study was needed to be conducted. The Resair 2 guidelines of 2005/6 went a step further and declared that the (‘resuscitation of newborn infants with room air or oxygen’) study optimal oxygen concentration for newborn resuscitation is not was conducted with enrollment of 609 infants from 10 centers in known.30 At that time, much data had accumulated regarding the India, Egypt, Spain, Philippines, Estonia and Norway between 1994 toxic effects of pure oxygen resuscitation, and many of us regarded and 1996.18 Findings of the Resair 2 study confirmed the results of these guidelines to be conservative. However, these guidelines gave the pilot study that newborn infants in need of resuscitation at freedom to every country, institution and clinician to choose 18 birth could be resuscitated effectively with room air. In addition, the initial FiO2 considered optimal for newborn resuscitation in the Resair 2 study showed a trend toward reduced neonatal the given situation. This explains why some institutions started mortality in neonates resuscitated in room air compared with those using 21% oxygen and others 100% oxygen for newborn resuscitated with 100% oxygen (odds ratio 0.69; 95% confidence resuscitation, yet everybody was referring to the same guidelines. interval 0.44 to 1.06). Further, Apgar scores at 5 min were significantly higher in neonates resuscitated in room air compared with those resuscitated with 100% oxygen. Five years later, we Meta-analyses and systematic reviews published a follow-up study of a subset of the Resair 2 babies, To date, four meta-analyses and systematic reviews have been showing that neurodevelopmental outcomes at 18 to 24 months of published on the use of 21 or 100% oxygen in term and late age were not different in surviving babies between the groups.19 preterm infants in need of resuscitation.31–34 In the view of the

Journal of Perinatology Oxygen to resuscitate term infants OD Saugstad S48 available data, all these papers have come to similar conclusions: Finland, Russia, Spain, The Netherlands42 and the United 21% is as efficient as 100% oxygen in restoring heart rate and Kingdom43 have changed their national guidelines to start spontaneous ventilation in depressed newborn infants. Further, all with 21% oxygen when resuscitation of newborns is required. of the meta-analyses and systematic reviews conclude that neonatal Increasingly, more units in the United States also have switched to mortality is significantly reduced in those resuscitated with 21% the low-oxygen approach. In many European centers, 21% oxygen compared with neonates resuscitated with 100% oxygen. The most has been now routine for over 15 years, and very few centers recently published meta-analysis included 10 studies and 2134 start with administration of 100% oxygen now. Many centers not infants enrolled. Neonatal mortality was 12.8% in the group starting with 21% oxygen start, for instance, with 40% oxygen resuscitated in 100% oxygen and 8.2% in the group of patients and turn down the FiO2, according to the clinical condition or resuscitated with 21% oxygen, giving a relative risk for neonatal pulse oximetry readings. However, there are no data available death of 0.69 (95% confidence interval: 0.54 to 0.82) in favor of the on the efficacy and safety of this ‘in between’ approach. 21% group. Six of the studies included in this analysis, enrolling 449 babies, were strictly randomized. All of these studies were from Europe, mainly from Spain. In this subset, relative risk for Preterm infants neonatal death in favor of 21% was as low as 0.32 (95% confidence The Netherlands was the first country to include preterm infants in interval: 0.12 to 0.85). This indicates an almost 70% reduction their room-air resuscitation guidelines.42 However, contrary to that in neonatal death by switching from 100 to 21% oxygen for in late preterm and term neonates, there is not much evidence to 31 newborn resuscitation in developed countries. In the same article, support exact recommendations for the initial FiO2 when very low a tendency toward a reduction in hypoxic ischemic encephalopathy birth weight infants need resuscitation at birth. There are presently was also found, with relative risk of 0.88 for the babies resuscitated three smaller randomized studies44–46 and an observational study47 in 21% oxygen compared with the neonates resuscitated in 100% published, and their findings suggest that the smallest infants oxygen, with a 95% confidence interval of 0.72 to 1.08. This is in should also be started with a low-oxygen approach. Findings of a agreement with the findings of numerous animal experiments recent study indicate that it is feasible to initiate delivery room showing that a brief exposure of oxygen following hypoxia has stabilization with <100% oxygen in very low birth weight infants 20,21,24,25 dramatic deleterious effects on the newborn brain. when the FiO2 is being adjusted according to postductal SaO2 It has been shown that the first breath is delayed by 30 s in values.48 In addition, preterm infants <35 weeks of gestation in babies resuscitated with 100% compared with those resuscitated need of resuscitation had evidence of lower levels of oxidative stress with 21% oxygen. Heart rate at 90 s and the 5-m Apgar score were when FiO2 was titrated according to pulse oximetry than when 31 49 also lower when 100% oxygen was applied. The present 100% O2 was used. From the emerging data it seems that an FiO2 resuscitation algorithm is based on exactly 30-s steps. This means of 1.0 or 0.9 is too high for preterm infants in need of stabilization/ that an infant who is not responding properly to ventilation after resuscitation at birth, whereas 0.21, in many cases, is too low. 30 s is moved to chest compressions, and after another 30 s is given However, an FiO2 of 0.3 seems to be sufficient in most cases for the epinephrine.30 The 30-s delay in restoring ventilation in the babies initiation of the resuscitation process and might result in fewer 46 exposed to 100% oxygen therefore, indicates that more of these complications than starting with an FiO2 of 0.9. A planned babies will be receiving chest compressions and medications such large multicenter study (‘Presox’ trial) will explore this issue in as epinephrine. more detail.50 Two studies in newborn animals35,36 and one in adult rats37 have shown that, even in cardiac arrest, room air is as efficient as Time for change 100% O2 in establishing the return of spontaneous circulation. A recent study in newborn mice with respiratory arrest did, however, There has been a slow but dramatic switch from a high- to 38 show a better effect of administration of 100% O2 than 21% O2. a low-oxygen approach for the resuscitation of term neonates However, this study was not a resuscitation study because no worldwide since the last 15 years or so. Meta-analyses but not a ventilation was provided.39 single randomized trial indicate that room air resuscitation can reduce neonatal mortality by 30 to 40%. As more than 4 million newborn infants have birth asphyxia globally each year and Why is oxygen still used for resuscitation of term babies? approximately 1 million die, room-air resuscitation might save More and more units in many countries have changed their more than 100 000 newborn lives each year. The understanding practice from a high- to a low-oxygen resuscitation approach. that newborn infants can be resuscitated with ambient air has The first country that changed its guidelines to start resuscitation opened up new resuscitation projects in underdeveloped countries with 21% oxygen was Canada in 200640 followed by Australia41 and has thus paved the way for a new momentum and interest in in 2007. To date I have information that Belgium, Sweden, establishing resuscitation programs in these countries as well.

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Finally, in his review, Obladen states: ‘When in 1780 Chaussier 11 Rootwelt T, Odden JP, Hall C, Ganes T, Saugstad OD. Cerebral blood flow and evoked initiated oxygen treatment for neonatal asphyxia, it just seemed potentials during reoxygenation with 21 or 100% O2 in newborn pigs. J Appl Physiol logical to him. When in 2005 the ILCOR guidelines, European 1993; 75: 2054–2060. guidelines, and Cochrane Database gave three different 12 Feet BA, Medbo¨ S, Rootwelt T, Ganes T, Saugstad OD. Hypoxemic resuscitation in newborn piglets: recovery of somatosensory evoked potentials, hypoxanthine, and recommendations for the use of oxygen in neonatal resuscitation, acid-base balance. Pediatr Res 1998; 43: 690–696. the weakness of modern, purportedly evidence-based medicine was 13 Feet BA, Yu XQ, Rootwelt T, Oyasaeter S, Saugstad OD. Effects of hypoxemia revealed.’1 Although clearly more data are needed, sufficient and reoxygenation with 21 or 100% oxygen in newborn piglets: extracellular evidence supports the ongoing change in attitude toward the use of hypoxanthine in cerebral cortex and femoral muscle. Crit Care Med 1997; 25: less oxygen in the resuscitation of term neonates. 1384–1391. 14 Kutzsche S, Ilves P, Kirkeby OJ, Saugstad OD. Hydrogen peroxide production in leukocytes during cerebral hypoxia and reoxygenation with 100 or 21% oxygen in newborn piglets. Pediatr Res 2001; 49: 834–842. Conclusion 15 Kutzsche S, Kirkeby OJ, Rise IR, Saugstad OD. Effects of hypoxia and reoxygenation Resuscitation of term neonates should no longer be initiated with with 21 and 100%-oxygen on cerebral nitric oxide concentration and microcirculation in newborn piglets. Biol Neonate 1999; 76: 153–167. 100% oxygen. For babies of X32-week gestational age with 16 Medb S, Yu XQ, Asberg A, Saugstad OD. Pulmonary hemodynamics and plasma healthy lungs, it is safe, in most cases, to start resuscitation with endothelin-1 during hypoxemia and reoxygenation with room air or 100% oxygen in 21% O2. If a higher FiO2 is chosen, oxygen concentration should a piglet model. Pediatr Res 1998; 44: 843–849. quickly be turned down according to the response of the patient 17 Ramji S, Ahuja S, Thirupuram S, Rootwelt T, Rooth G, Saugstad OD. Resuscitation of asphyxic newborn infants with room air or 100% oxygen. Pediatr Res 1993; 34: guided by the SaO2 and heart rate. For newborns of <32-week 809–812. gestational age, the optimal FiO2 to initiate resuscitation is not 18 Saugstad OD, Rootwelt T, Aalen O. Resuscitation of asphyxiated newborn infants with known; however, resuscitation may be started with an FiO2 between room air or oxygen: an international controlled trial: the Resair 2 study. Pediatrics 0.21.to 0.30 and then titrated according to the patient’s response. 1998; 102: e1. 19 Saugstad OD, Ramji S, Irani SF, El-Meneza S, Hernandez EA, Vento M et al. Resuscitation of newborn infants with 21 or 100% oxygen: follow-up at 18 to 24 months. Pediatrics 2003; 112: 296–300. Conflict of interest 20 Munkeby BH, Brke WB, Bjrnland K, Sikkeland LI, Borge GI, Halvorsen B et al. The author declares no conflict of interest. Resuscitation with 100% O2 increases cerebral injury in hypoxemic piglets. Pediatr Res 2004; 56: 783–790. 21 Solberg R, Andresen JH, Pettersen S, Wright MS, Munkeby BH, Charrat E et al. Resuscitation of hypoxic newborn piglets with supplementary oxygen induces dose- References dependent increase in matrix metalloproteinase-activity and down-regulates vital genes. 1 Obladen M. History of neonatal resuscitation. Part 2: oxygen and other drugs. Pediatr Res 2010; 67(3): 250–256. Neonatology 2009; 95: 91–96. 22 Lakshminrusimha S, Russell JA, Steinhorn RH, Swartz DD, Ryan RM, Gugino SF et al. 2 Klaus M, Meyer BP. Oxygen therapy for the newborn. Pediatr Clin North Am 1966; 13: Pulmonary hemodynamics in neonatal lambs resuscitated with 21, 50, and 100% 731–752. oxygen. Pediatr Res 2007; 62: 313–318. 3 Emergency Cardiac Care Committee Subcommittees of the American Heart Association. 23 Lakshminrusimha S, Russell JA, Steinhorn RH, Ryan RM, Gugino SF, Morin 3rd FC Guidelines for cardiopulmonary resuscitation and emergency cardiac care, IV: pediatric et al. Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen basic life support. J Am Med Assoc 1992; 268: 2276–2281. resuscitation. Pediatr Res 2006; 59: 137–141.

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