Use and misuse of oxygen. Clinics in Perinatology 2012

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The Use and Misuseof Oxygen Duringthe Neonatal Period

Máximo Vento, MD, PhDa,b,*, Javier Escobar, PhDb,María Cernada, MDb, Raquel Escrig, MDa, Marta Aguar, MDa

INTRODUCTION

Life as we know it in biologic systems depends on the ability of overcoming entropywhich is the natural tendency towards molecular disorder. To overcoming entropya great amount of energy is necessary. The present review addresses the relevanceof aerobic metabolism as the most efficient means of obtaining energy frommetabolicsubstrates rendering oxygen indispensable for life. However, as a counterpart nega-tive aspects of oxidative metabolism will also be addressed.

AEROBIC METABOLISM

Oxygen is one of the most abundant elements in nature and also one of the mostwidely used drugs in neonatology (Fig. 1).1 Because of its specific properties, oxygenhas evolved to become indispensable to sustain life in multicellular organisms. Hence,oxygen is completely available, diffuses easily across biologic membranes, and canbind to heme in proteins, such as hemoglobin and cytochromes in mitochondria.2

Of note, with the concourse of oxygen, cells are capable to build up sufficient ATPtomeet their energy needs in the oxidative phosphorylation process. Briefly, energizedelectrons liberated in the tricarboxylic cycle (Krebs cycle) are transferred to the elec-tron transport chain (ETC) by specific transporters (nicotinamide adenine dinucleotide,flavin adenine dinucleotide). This energy is used by components of the ETC to extrudeprotons to the intermembrane space, thus creating a mitochondrial transmembranepotential (Jm). When protons are pumped back to the mitochondrial inner space,

Disclosure Statement: None of the authors of this article has any commercial or financial relationto disclose.a Division of Neonatology, University & Polytechnic Hospital La Fe, Valencia, Spainb Neonatal Research Unit, Health Research Institute Hospital La Fe, Valencia, Spain* Corresponding author. Division of Neonatology, University& Polytechnic Hospital La Fe, BulevarSur s/n, 46026 Valencia, Spain.E-mail address: [email protected]

KEYWORDS

� Oxygen � Oxidative stress � Newborn � Pulse oximetry� Oxygen saturation � Oxygen toxicity

Clin Perinatol 39 (2012) 165–176doi:10.1016/j.clp.2011.12.014 perinatology.theclinics.com0095-5108/12/$ – see front matter � 2012 Elsevier Inc. All rights reserved.


the energy liberated in this process is used by the ATP synthase complex to rebuildATP. Simultaneously, ground molecular dioxygen is completely reduced by 4 elec-trons.3 Remarkably, aerobic metabolism (ie, with the concourse of oxygen) is 20 timesmore efficient than anaerobic metabolism, thus providing sufficient energy for cellgrowth, development, and reproduction (eg, 1 molecule of glucose forms 34 mole-cules of ATP through the aerobic pathway and 4 through the anaerobic). Specific cells,such as neurons, are unable to accumulate energy, however, and can survive for onlya few minutes under hypoxic conditions, rendering oxygen indispensable for centralnervous system survival.1

Oxygen Free Radicals

The oxygen molecule has 2 unpaired electrons in its outer shell that prevent it fromforming new chemical bonds (Fig. 2). Partial reduction of oxygen with just 1 electronat a time will lead to the formation of reactive oxygen species (ROS), such as anionsuperoxide (O2

�), hydroxyl radical (OH�), and hydrogen peroxide (H2O2). Some ofthese chemicals are highly reactive species known as free radicals. In the presenceof nitric oxide, oxygen free radicals will react, forming reactive nitrogen species(RNS), such as peroxynitrite (ONOO–). ROS and RNS are potent oxidizing and

Fig. 1. Oxidative phosphorylation occurs in mitochondria, where highly energized electronsliberated in the Krebs cycle are transported to the ETC, creating a mitochondrial transmem-brane potential. Extruded protons are reintroduced in the intermembrane space by theaction of ATP-synthase. Energy liberated in this process is used to rebuild ATP while electronsare captured by oxygen, which becomes fully reduced.

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reducing agents with an extremely short half-life that will react with any nearbystanding cellular structure, thereby altering their structure and function. Free radicalsare atomic or molecular species capable of independent existence that contain one ormore unpaired electrons in their molecular orbitals. They are able, therefore, to oxidizecellular membranes, structural proteins, enzymes, and nucleic acids.3,4

Antioxidant Defenses

Biologic systems using aerobic metabolism have been able to survive the deleteriouseffects of free radicals because a large number of enzymatic and nonenzymatic anti-oxidants have evolved (see Fig. 2). The antioxidant enzymes are represented by thefamily of superoxide dismutases (SOD) formed by Cu-Zn SOD or soluble SOD1located in the cytosol, Mn-SOD or SOD2 located in the mitochondria, and extracel-lular, or SOD3. In addition, catalase, glutathione peroxidases, and glucose 6-phos-phate dehydrogenase together constitute the most relevant enzymatic defenseagainst free radicals. The major nonenzymatic intracellular antioxidant is glutathione(GSH), an ubiquitous tripeptide formed by g-glutamine, L-cysteine, and glycine.GSH is able to reduce free radicals by establishing a disulfur bond with anotherGSH molecule, forming oxidized glutathione (GS 5 SG), thus providing 1 electron.Oxidized glutathione is reduced again to its reduced form (GSH) by the action of gluta-thione reductase (GSH-reductase) with the electrons provided by nicotinamideadenine dinucleotide phosphate (NADPH). Other relevant nonenzymatic antioxidantsare proteins that bind transition metals, such as transferrin and ceruloplasmin, or

O::O

O2¯ •

H2O2

OH•

O2

e¯

e¯

e¯

e¯

Superoxide

Hydrogen peroxide

HydroxylFenton chemistry

[Fe++]

[Fe+++]Haber-Weiss reaction

[O2¯ •]

NO•

ONOO•

(Ground dioxygen)

Peroxynitrite

[CuZnSOD][MnSOD], [EcSOD]

[CAT], [GPx][TRx], [PRx]

GSH

GSSG2e¯

H2O

GR

(1)

(2)

(3)

(4)

(5)

(5)

Fig. 2. Oxygen (1) is partially reduced by the action of a series of enzymatic complexes toanion superoxide (2). Anion superoxide is dismutated by superoxide dismutases (SOD) tohydrogen peroxide (3), which is turn is transformed into water and oxygen by the actionof catalases (CAT) and glutathione peroxidase (GPX). In the presence of transition metals(eg, iron, copper), hydrogen peroxide can be transformed into hydroxyl radical (4). More-over, in the presence of nitric oxide (NO), anion superoxide can also be transformed intoperoxynitrite (5).

Use and Misuse of Oxygen 167


molecules that quench free radicals, such as uric acid and bilirubin and certain vita-mins, such as A and C.5,6

Oxidative Stress

The concept of oxidative stress refers to the imbalance between the formation of freeradicals and the capability of the biologic system to neutralize them. To evaluateoxidative stress, different biomarkers have been used. They may directly reflecta pro-oxidant or antioxidant status, such as GSH/GSSG ratio, one of the most reliableand used oxidative stress markers. Other biomarkers may reflect direct damage tothe cell structures. Hence, for lipid peroxidation, malondialdehyde or n-aldehydes(eg, 4-hydroxy-nonenal) have been widely used. Nucleic acid damage is generally re-flected by guanosine base oxidation products, such as 8-oxo-dyhydroguanosine. Iso-prostanes and isofurans have evolved as some of the most reliable markers ofoxidative stress and reflect non–cyclo-oxygenase peroxidation of polyunsaturatedfatty acids and, intriguingly, have important vasoactive properties. Oxidation of circu-lating amino acids can be measured by the action of free radicals on specific targets,such as phenylalanine. The oxidation of phenylalanine derived from the attack ofhydroxyl radicals leads to its conversion into ortho-tyrosine (o-tyr) and meta-tyrosine (met-tyr), both highly specific markers of oxidative stress. Other markers ofprotein oxidation are known as carbonyl compounds (C 5 O), whose presence ingreater amounts in the lung alveolar lavage fluid or tracheal aspiration significantlycorrelate with development of chronic lung disease.4,5

Inflammatory Response and Redox Signaling

In addition to causing oxidative damage to cell structures, ROS and RNS are capableof triggering an inflammatory response in the cells promoting the transformation ofI-kB into NF-kB, a transcription factor for multiple inflammation-related genes. ROSand RNS are also capable of activating tumor necrosis factor–alpha, essential in theinflammatory response as well as in the activation of apoptosis.5 To do so, ROShave to act on redox mechanisms that function in control of gene expression, cellproliferation, and apoptosis. Hydrogen peroxide especially, but also other ROSprovide amechanism to reversibly oxidize/reduce signaling proteins providing ameansfor control of protein activity, protein-protein interaction, protein trafficking, andprotein-DNA interaction.7

FETAL TO NEONATAL TRANSITION

Fetal life develops in an environment that is relatively hypoxic compared with theextrauterine world; hence, arterial partial pressure of oxygen (paO2) in utero is of 25to 35 mm Hg in the general circulation and even less (17–19 mm Hg) in the pulmonarycirculation.8 Although seemingly isolated from the external milieu, the fetus is highlysusceptible to changes in oxygenation induced in the mother. Hence, recent studieshave shown that the paO2 of fetuses whose mothers received oxygen supplementa-tion during labor was significantly increased as compared with nonsupplementedcontrols; moreover, the former also had significantly increased concentrations ofbiomarkers of oxidative stress, such as malondialdehyde and F2-isoprostanes incord blood.9 Immediately after birth, with the initiation of spontaneous respirationand alveolar-capillary gas exchange, paO2 rises to 80 to 90 mm Hg in the first 5 to10 minutes of life. This abrupt change causes the physiologic oxidative stress neces-sary to trigger the expression of a number of significant genes necessary for postnataladaptation.10 The first studies of fetal pulse oximetry (SpO2) during labor revealed that

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normal values were approximately 58% � 10%. Studies performed in term newborninfants have shown that SpO2 does not reach stable values of 85% or higher until 5minutes after birth, and some healthy newborn infants need even more time, espe-cially if they are born by cesarean section. In addition, preterm infants, especiallyextremely low birth weight (ELBW) infants, will not reach an SpO2 of 85% or higheruntil at least 10 to 15 minutes after birth (Fig. 3).11

Arterial Oxygen Saturation Nomogram

Dawson and colleagues,12 in 3 prospective observational studies using the samemethodology, separately enrolled 468 newly born infants with gestational agesranging from 25 to 42 weeks who did not receive oxygen at birth. Thus, arterial oxygensaturation as measured by pulse oximetry was retrieved from the first minute afterbirth using last-generation monitors set at maximum sensitivity attached to the rightwrist to continuously measure preductal oxygen saturation until newborn infantsachieved clinical stabilization. Thereafter, the 3 data sets were assembled into a graphthat represents a reference range for SpO2 for healthy babies of fewer than 42 weeksof gestation in the first 10 minutes after birth (Fig. 4).12 As shown in the nomogram, ittook a median of 7.9 minutes (interquartile range 5.0–10.0) to reach an SpO2 higherthan 90%, and preterm infants needed significantly more time to reach this satura-tion.12 At present, Dawson and colleagues’13 oxygen saturation nomogram representsthe best estimate of the most appropriate SpO2 targets for term but especially forpreterm infants during the first minutes of life.

Oxygen Administration in the Delivery Room

In experimental and clinical studies, it has been shown that the use of room air (21%oxygen) offers substantial advantages over the use of 100% oxygen, as had been

Fig. 3. Oxygen saturation in the first 10 minutes of life as measured by pulse oximetry inhealthy term and preterm babies with the sensor located on the right wrist (preductal) orin term babies located on the feet (postductal). Values expressed in the graph have beenretrieved from the database of the first author (M.V.) and have not been previouslypublished.



traditionally recommended in the resuscitation of depressed newborn infants. Thus,ameta-analysis retrieving published evidence concluded that the use of roomair signif-icantly reduces mortality in asphyxiated neonates14; moreover, air-resuscitation alsoshortens the time needed to initiate spontaneous respiration, improves Apgar score,and reduces oxidative stress and oxidative damage to vital organs, such as myocar-dium and kidneys.15,16 As a consequence, in 2010 the International Liaison Committeeon Resuscitation guidelines recommended the use of air as the initial gas admixture forthe depressed neonate; moreover, both pulse oximetry monitoring of SpO2 and titra-tion of the inspiratory fraction of oxygen (FIO2) to avoid hyperoxic or hypoxic damagewere also encouraged.17

Preterm babies do not generally suffer from birth asphyxia; however, they experi-ence difficulties in adapting to the extrauterine environment because of lung andthoracic cage immaturity. Hence, a significant proportion of preterm infants willneed proactive interventions in the delivery room. Positive-pressure ventilation isthe cornerstone of preterm resuscitation. Initial ventilation is performed in sponta-neous breathing neonates with continuous positive-pressure ventilation, applying 4to 8 cm H2O.18 Randomized controlled studies have shown that it is feasible to startresuscitation even in extremely low gestational age neonates using an initial FIO2 of21% to 30%, as long as the inspiratory fraction of oxygen is titrated against SpO2

and the heart rate is kept within normal limits.19–22

Reliable preductal readings immediately after birth can be rapidly obtained (60–90seconds) if caregivers have been adequately trained. Data are most quickly availableif the device is applied in the following order: (1) turn on the oximeter, (2) apply thesensor to the infant’s right hand or wrist to reflect oxygen saturation of blood goingto the brain, (3) connect the sensor to the oximeter cable to avoid erroneous calibra-tion by the device, and (4) shield the sensor from light.13 Once effective ventilation hasbeen established and SpO2 readings are available, FIO2 should be titrated againstSpO2 readings in the pulse oximeter adjusting the air/oxygen blender to avoid

Fig. 4. Oxygen saturation reference range as measured by preductal pulse oximetry ex-pressed in percentiles for the first 10 minutes after birth in healthy human neonates notneeding resuscitation in the delivery room with gestational ages between 25 and 42 weeks.(Data from Dawson JA, Kamlin CO, Vento M, et al. Defining the reference range for oxygensaturation for infants after birth. Pediatrics 2010;125:e1340–7.)

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hyperoxia and hypoxia. Hence, if SpO2 is below the 10th percentile, then FIO2 shouldbe increased in 10% increments every 30 seconds until SpO2 reaches the 10th to 50thpercentile, always avoiding an SpO2 greater than the 90th percentile.13 Although rec-ommended by experts in the field, however, this approach is not evidence-based andno randomized controlled trial to date has informed on which SpO2 targets would besafer for preterm infants in the first minutes after birth. In this regard, the AmericanHeart Association has defined the target ranges for 1, 2, 3, 4, 5, and 10 minutes afterbirth at 60% to 65%, 65% to 70%, 70% to 75%, 75% to 80%, 80% to 85%, and 85%to 90%, respectively.17 Notwithstanding, randomized controlled studies in preterminfants have shown that the use of a lower oxygen load during resuscitation signifi-cantly decreases oxidative stress and improves clinical outcome.20,22 Hence, untilsufficiently powered studies are available, our aim should be to reduce the oxygenload during resuscitation in the first minutes of life, trying to adjust the SpO2 to thereference charts that, at present, are our best estimate of the optimal oxygenationtargets in preterm infants.

OXYGEN DURING NEONATAL CARE IN THE NICU

The conundrum regarding the establishment of upper and lower limits of oxygen satu-ration, especially in ELBW infants, is still open. ELBW infants are very sensitive to bothhyperoxia, which may especially lead to lung and retinal damage, and to hypoxia,which may cause white matter injury.23 Studies that have compared different limitsfor SpO2 have concluded that neonatal units maintaining ELBW infants within lowsaturation limits (85%–95%) have a significantly lower incidence (w50%) of retinop-athy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) than those unitsallowing SpO2 to rise to higher limits (>95%).24–26 The extremely preterm (�28 weeks’gestation) lung is sensitive to oxidative stress because of (1) immature antioxidantdefense system; (2) lack of surfactant, which prompts the use of mechanical ventila-tion; (3) tendency toward infection (already in utero or manipulation in the NICU); or (4)presence of circulating free iron.27 A connection between oxygen, oxidative stress,and later appearance of BPD has been substantiated in different studies. Thus,preterm neonates who later developed BPD exhibited elevated concentrations inblood and tracheal aspirates of carbonyl adducts, which represent by-products ofthe attack of oxygen free radicals on structural and functional proteins of thelung.28–30 Similarly, elevated plasma isofurans immediately after birth from higheroxygen load and F2a isoprostanes in the first week after birth have also been associ-ated with later development of BPD and periventricular leukomalacia.22,31 In additionto the acute effect of ROS, a body of evidence indicates that ROS act as triggeringmolecules for transcription factor activation and could be responsible for regulatingcell growth, differentiation, chemotaxis, inflammatory response, or apoptosis.7 Hence,hyperoxia exposure, especially in preterm infants, leads to the release of specificmediators, such as vascular endothelial growth factor (VEGF) and angiopoietin 2,capable of disrupting the alveolar-capillary membrane and thus leading to pulmonaryedema and subsequent lung injury. Other cytokines are also released from lung cells,attracting inflammatory cells to the lung. These inflammatory cells, as well as hyper-oxia per se, release ROS, which can initiate the mitochondrial-dependent cell deathpathway.32 In the Benefits of Oxygen Saturation Targeting (BOOST) trial, the effectof higher (95%–98%) versus lower (91%–94%) targeted saturations for babies atfewer than 30 weeks of gestation was compared. In the BOOST trial, the use of higherSpO2 was associated with an increased length of oxygen therapy, a higher rate ofchronic lung disease, and a greater frequency of babies discharged on home oxygen



therapy. At the same time, it did not improve neurodevelopment or somatic growth.25

In another randomized controlled trial, the STOP-ROP trial (Supplemental TherapeuticOxygen for Pre-threshold Retinopathy of Prematurity), an SpO2 ranging from 89% to94% was compared with a range of 95% to 99% in preterm babies with prethresholdROP for a minimum of 2 weeks.33 The beneficial effect of a higher SpO2 on the evolu-tion of eye disease was minimal, whereas the negative effects, such as prolongedhospitalization, respiratory morbidity, and prolonged need for oxygen supplementa-tion, were significantly higher.33 In addition to the well-known risks of hyperoxia,recent randomized controlled trials have illustrated the risk of keeping extremelypreterm infants within lower ranges of SpO2. In this regard, in the SUPPORT trial(Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial), it wasconfirmed that surviving ELBW infants randomly assigned to lower SpO2 target ranges(85%–89%) had a lower risk of ROP (8.6% vs 17.9%; P<.01) than those in the highertarget group (91%–95%)34; however, increased mortality in the low-saturation group(19.9% vs 16.2%; P<.04) has raised serious concerns about keeping very preterminfants at lower oxygen saturation limits.34 In addition, the BOOST II trial performedin the United Kingdom, Australia, and New Zealand (n 5 2315), in which saturationtarget ranges compared were also of 85% to 89% versus 91% to 95%, it was shownthat with the updated calibration algorithm used in the pulse-oximeter devices usedin these trials, the range groups targeted for lower saturation had significantlylower survival rates than those targeted for higher saturation limits (17.3% vs14.4%; P<.015). The trial was therefore interrupted.35 Hence, although at presentthere is no conclusive evidence to consider 85% an unsafe lower saturation limit, greatconcern relative to increased mortality, especially for infants at fewer than 28 weeks ofgestation, has been expressed.34,35 Seemingly, there is no fixed SpO2 range oroxygen supply that safely satisfies metabolic demands of infants born at differentgestational ages; moreover, even for a given gestational age, postnatal age is alsoa relevant factor to be taken into consideration when establishing oxygenation limits.

EVOLVING OXYGEN NEEDS IN THE FIRST WEEKS OF LIFE AND NEWMETABOLIC INDICES

Recent studies have suggested that it would be possible to differentiate between 2different periods with different oxygen limits.36 Very preterm infants at fewer than 32weeks of postconceptional age would theoretically benefit from lower SpO2 limits(eg, 85%–95%). In a phase of rapid vascular growth and extreme tissue sensitivityto oxygen because of an immature antioxidant defense system, the use of higheroxygen limits would lead to oxidative stress and inflammation in the lung, intestine,or brain, leading to BPD, necrotizing enterocolitis, or intraperiventricular hemorrhage.Older neonates (>32 weeks postconceptional age) with a more mature antioxidantsystem and a tendency toward hyperproliferation of the vascular bed of the retina,owing to a relative hypoxia of the retinal tissue, would benefit from higher SpO2 ranges(98%–99%), however. This latter approach has not been conclusively established.36

Fig. 5 summarizes what would be consistent with the available literature. Hence, inthe immediate postnatal period and independently from gestational age, the targetsaturation in the fetal to neonatal transition, and in the first hours thereafter, SpO2

safety limits are seemingly of 85% to 90%; however, as deduced from the SUPPORTand BOOST II trials, as the preterm baby matures, metabolic necessities increase, asdoes the risk for hypoxemia.34,35 In this regard, it would be extremely useful to have atour disposal functional and noninvasive biomarkers that would allow clinicians tomonitor cell aerobic metabolism and evaluate the response to intervention. Of note,

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experimental studies performed in situations of hypoxia/reoxygenation have shownthat traditional biomarkers of hypoxemia, such as lactic acid, do not significantlycorrelate with intensity and especially duration of hypoxia. Furthermore, glycine/branched chained amino acids (BCC) or alanine/BCC ratios are far better predictorsof duration of hypoxia. In addition, if metabolites from the Krebs cycle, such as succi-nate and propionyl-L-carnitine, were also taken into consideration, the correlation withthe duration of cell hypoxia was further increased.37 Research performed in the exper-imental and clinical setting show that in the near future other biomarkers will help theclinician in assessing patients’ aerobic metabolism, cell oxygen needs, and responseto interventions. Hence, levels of growth factors (eg, insulinlike growth factor, VEGF, ormetabolite ratios) might be used in the future to attain reliable information relative tocell oxygenation and, more importantly, to advert of the initiation of retinal vascularproliferation.36

GOING HOME ON OXYGEN

Chronic lung disease and prolonged oxygen needs among extremely preterm infants(�28 weeks’ gestation) is still a matter of concern. Of note, a relevant number ofthese babies are still being discharged home from the hospital on supplementaloxygen.38 The goal of home oxygen therapy is to prevent the effects of chronichypoxemia, which include pulmonary vasoconstriction leading to pulmonary hyper-tension, bronchial constriction leading to airway obstruction, and changes in growthof pulmonary and ocular vasculature. Hence, improved oxygenation may lead toimproved lung growth and repair, better nutritional status, and somatic growth.39

Although there is a great variation among institutions regarding indications forhome oxygen use, in a recent retrospective study including 8167 preterm infantsbetween 23 and 31 weeks of gestation born in 280 NICUs in the United States,home use of oxygen was recorded in 59% of infants of 23 to 24 weeks of gestationand in 8% of infants of 29 to 31 weeks of gestation.40 Moreover, the authors under-scored that gestational age was by far the most significant risk factor for being dis-charged on oxygen; however, other relevant factors included small for gestational

Fig. 5. Suggested SpO2 ranges for preterm infants in the first weeks after birth, as deducedfrom the published literature (see text).



age, congenital anomalies, need for mechanical ventilation or for FiO2 higher than40% in the first 72 hours after birth, and patent ductus arteriosus.40 Remarkably,many of these infants are going to experience acute life-threatening events athome with high risk for their physical and especially neurologic integrity.41 As a safetymeasure, air tests can be performed before discharge. The purpose of this approachis to determine the nadir of SpO2 reached in room air after supplemental oxygen hasbeen suppressed. In most units, a minimum SpO2 of higher than 80% should bemaintained in air for 30 minutes before discharge, and after discharge, clinical signs,such as respiratory rate and growth, are combined with continuous overnight oxime-try (or polysomnography) where available.39

To date, with our present knowledge of oxygen needs and oxygen-derived compli-cations secondary to hyperoxia and/or hypoxia, babies with chronic neonatal lungdisease should be targeted for SpO2 range of 93% to 95%.

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