Description of the condition
The administration of supplemental oxygen has a long history in neonatal care (Wilson 1942; Tin 2007). Oxygen was used liberally for the first time in neonates in the 1930s when an oxygen unit was described for preterm infants (Raju 1999). The use of oxygen in preterm and low birth weight infants suffering respiratory insufficiency has resulted in significant healthcare benefits, such as reduced mortality and spastic diplegia (Avery 1960; McDonald 1963), but has also been associated with significant deleterious effects such as retinopathy of prematurity and lung toxicity (Duc 1992).
Improvements in technology in the past few decades have led to the increased survival of preterm and low birth weight infants. One of these advances is the ability to measure oxygen levels more accurately. Despite the exceedingly common use of supplemental oxygen in this population of infants, there is little consensus as to the optimal levels of oxygen for maximising short- or long-term growth and development, while minimising harmful effects (Poets 1998; McIntosh 2001; Silverman 2004).
ADVERSE CONSEQUENCES OF LIBERAL AND RESTRICTED USE OF OXYGEN
The adverse consequences of liberal oxygen use were recognised in the early 1940s. Terry 1944 described a type of blindness in preterm infants characterised by thick fibrotic membrane in the retrolental space. In 1951 the role of supplemental oxygen in the aetiology of 'retrolental fibroplasia' (RF) was first suggested (Campbell 1951). By 1954, RF had blinded about 10,000 infants (Silverman 1980; Silverman 2004). From 1954 to 1956, three randomised trials (Lanman 1954; Patz 1954; Kinsey 1956), enrolling 341 infants, proved that breathing unrestricted concentrations of inspired oxygen was a major cause of RF (Askie 2009). Throughout this period, oxygen administration was guided by the clinical observations of skin colour, as well as the rate, regularity and work of breathing. It was not until the 1960s and 1970s that sampling of blood gases, transcutaneous oxygen monitoring and later pulse oximetry became available for more precise monitoring of oxygen levels (Walsh 2009). An early prospective cohort study, reported in 1977, was unable to establish a causal relationship between arterial oxygen tension and (what is now known as) retinopathy of prematurity (ROP), but did reveal that the most relevant factors for developing ROP were birth weight less than 1200 grams and length of exposure to supplemental oxygen (Kinsey 1977).
As a consequence of the RF blindness epidemic in the 1960s, the use of oxygen was drastically limited, usually to less than 40% inspired oxygen, even for preterm infants with respiratory distress, allowing them to become severely hypoxaemic and leading to a substantial increase in the incidence of cerebral palsy (Usher 1961). In the next 20 years over 150,000 premature babies died of hypoxic respiratory failure (Avery 1960; McDonald 1964; Cross 1973; Bolton 1974). It is estimated that for every infant whose sight was saved, 16 died (Avery 1960; Silverman 2004) and many others developed spastic diplegia (McDonald 1964).
Description of the intervention
Multiple attempts have been made to establish the optimal oxygen levels in preterm infants, using a variety of technologies, in order to circumvent the adverse consequences of either restricted or liberal use of supplemental oxygen.
However, what constitutes an 'appropriate' level of oxygen for infants born preterm, who would otherwise be in-utero, remains unknown. The foetus is relatively hypoxic with haemoglobin (Hb) oxygen saturations of 65%, 55%, and 45% in the aorta, pulmonary artery and pulmonary vein, respectively. However it should be noted that foetal blood contains almost only foetal haemoglobin (HbF) which has an extraordinary affinity for oxygen and is therefore capable of capturing sufficient oxygen from the intervillous space to support foetal growth and metabolism (Gao 2010; Vento 2013).
In the 1980s and early 1990s the use of transcutaneous oxygen monitoring became available. A study of transcutaneous oxygen monitoring (TcO₂) in preterm infants confirmed that ROP occurred more often when longer periods of time were spent with a TcO₂ above 80 mm Hg, but did not determine if another limit was safer (Flynn 1992). A partial pressure of arterial oxygen (PaO₂) range of 50 to 80 mmHg became widely accepted as an appropriate level to target (AAP 1988; McIntosh 2001; AAP 2002), but this was based on professional consensus rather than on evidence.
In the 1990s the use of pulse oximetry became a standard of care and continuous monitoring has allowed more frequent titration of the oxygen concentration administered. Pulse oximetry (SpO₂) refers to the estimation of the oxygen saturation of arterial blood using a device that measures the pulsatile changes in light transmission across a tissue bed. Pulse oximeters work on the principle that desaturated haemoglobin and oxygenated haemoglobin absorb light of different wavelengths (red and infrared). The oximeter emits light of these two wavelengths and measures absorption in the pulsatile element of the blood flow, thus producing a measure of the oxygen saturation of arterial blood separate from the non-pulsatile venous blood (Williams 1998). Pulse oximeters lack the heat-related side effects of transcutaneous oxygen monitors.
Despite the ease of use of pulse oximeters, translation of SpO₂ values into PaO₂ can be difficult to establish. The correlation between SpO₂ and PaO₂ is dependent on various physiologic circumstances such as affinity of Hb for oxygen which is significantly greater in foetal Hb. Thus, the higher the foetal Hb concentration the higher the SpO₂ would be for any given PaO₂ value. Castillo 2008 reported that in preterm infants for oxygen saturation values between 85% and 93%, the mean measured PaO₂ was 56 ± 14.7 mm Hg. Within this SpO₂ range, 87% of the samples had PaO₂ values of 40 to 80 mm Hg, 8.6% had values of less than 40 mm Hg, and 4.6% had values greater than 80 mm Hg. When the SpO₂ was greater than 93% the mean PaO₂ was 107.3 ± 59.3 mm Hg with 60% of values greater than 80 mm Hg.
The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity trial (STOP ROP 2000) used pulse oximetry to target a lower (89% to 94%) or higher (96% to 99%) oxygen saturation range in 649 preterm infants with prethreshold ROP who were 35 weeks postmenstrual age at randomisation. The higher range caused more adverse respiratory events including pneumonia, chronic lung disease requiring oxygen, and diuretic therapy. There was no statistically significant difference in the rate of progression to threshold ROP. The results of this trial are included in a separate Cochrane review entitled: Supplemental oxygen for the treatment of pre-threshold retinopathy of prematurity (Lloyd 2003). In the Benefits of Oxygen Saturation Targeting (BOOST) trial (Askie 2003), 358 infants born at less than 30 weeks’ gestation were randomly assigned, from three weeks or more after birth (at 32 weeks’ postmenstrual age) until they breathed air, to target an SpO₂ range of either 91% to 94% or 95% to 98% using offset oximeters. This trial found no evidence that higher SpO₂ targeting improved growth or development, but it did increase days of oxygen therapy and use of healthcare resources. Masked oximeters were adjusted to display values 2% lower or 2% higher than actual SpO₂ values. Staff were unaware of actual SpO₂ and targeted a masked range of 93% to 96%. The authors concluded that further large randomised trials were needed to determine how targeting different SpO₂ levels from the day of birth affects ROP, chronic lung disease, growth, disability and mortality (Askie 2003; Silverman 2004).
In transposing oxygen tensions of 50 to 80 mm Hg into equivalent arterial oxygen saturation, most clinicians have targeted functional SpO₂ 90% to 95% with a minimum acceptable SpO₂ of 85% (Anderson 2004). Hence the dichotomising of SpO₂ into 'higher' or 'lower' target ranges above or below a cut point of 90% appears reasonable. In the early 2000s, there were several observational studies that found lower SpO₂ was associated with less severe ROP; improved short-term respiration, growth and development outcomes; and either no apparent effect or a decrease in mortality (Tin 2001; Chow 2003; Anderson 2004). It should also be recognised that an intention to target a certain SpO₂ range does not guarantee that an infant's actual SpO₂ will always be maintained within that range. Most studies report that preterm infants receiving supplemental oxygen in a specified target range only remain in that range for about 30% to 50% of the time (Hagadorn 2006; Lim 2014).
To address the continuing uncertainty regarding the appropriate levels of oxygen saturation targeting for preterm infants with sufficient statistical reliability, the NeOProM Collaboration was formed in 2003. NeOProM is a prospective meta-analysis collaboration (Askie 2011) that includes five randomised trials (ACTRN12605000055606; ACTRN12605000253606; NCT00233324; ISRCTN00842661; ISRCTN62491227). These five trials prospectively (i.e. before the results of any of the trials were known) agreed to undertake their trials using very similar protocols, and have made a commitment to combine their individual participant data once their own trial's results are published. Representatives from each of these five trials and the NeOProM Collaboration are authors of this Cochrane Review.
There are two opposing concerns. Less inspired oxygen (targeting SpO₂ at 90% or less) may increase patent ductus arteriosus, pulmonary vascular resistance and apnoea, and may impair neurodevelopment (Newburger 1984; Skinner 1999; Subhedar 2000). More inspired oxygen (targeting SpO₂ greater than 90%) may increase severe ROP (Hellstrom 2013) and chronic lung disease (Warner 1998; Tin 2001; Sun 2002; Chow 2003; Anderson 2004). However, uncertainty remains as to the most appropriate range to target blood oxygen levels in preterm and low birth weight infants.
Two other related Cochrane reviews have summarised the findings on gradual versus abrupt (Askie 2001a) and early versus late discontinuation of oxygen therapy (Askie 2001b) in preterm or low birth weight infants. A meta-analysis of the available aggregate data from the five NeOProM trials was published by Saugstad 2014.
How the intervention might work
Oxygen is the most common therapy used in the care of very preterm infants. It has been associated with significant improvements in neonatal survival and reduced disability (Avery 1960). However, preterm infants are highly sensitive to the harmful biochemical and physiological effects of supplemental oxygen. Toxic oxygen radicals are increased in hyperoxia (Hellstrom 2001) and in re-oxygenation after hypoxaemia. Preterm infants are vulnerable to oxidative stress because they lack antioxidant protection (Hellstrom 2001) from plasma radical scavengers such as beta- carotene, antioxidant enzymes, such as glutathione peroxidase, and their red blood cells and cells of other organs (e.g. lungs) lack superoxide dismutase.
Targeting a higher oxygen level contributes to bronchopulmonary dysplasia (Warner 1998; Jobe 2001; Vento 2009; Kapadia 2013). Relatively recent epidemiological/observational studies (Tin 2001; Sun 2002; Chow 2003; Anderson 2004) and small randomised trials from the 1950s (Askie 2009) have suggested that targeting lower oxygen saturation levels may reduce severe ROP. The effects on death or neurodisability of targeting either lower or higher oxygen saturation levels from birth have not yet been fully assessed.
Why it is important to do this review
Extreme prematurity of less than 28 weeks’ gestation affects approximately 1% of births (Centre for Epi 2012). Although approximately 80% of these infants are discharged home alive (Chow 2013), they often sustain severe morbidity (Doyle 2010), including chronic lung disease, poor growth, respiratory illness, hospital re-admissions, visual deficits, cerebral palsy, neurodevelopmental disability and cognitive, educational and behavioural impairment (Anderson 2003). It is essential to determine whether the range of targeted SpO₂ levels affects the occurrence of such outcomes and, if possible, to determine the optimal range for management of the very vulnerable preterm infant. Very preterm infants account for a high proportion of the costs and disability from neonatal intensive care (Sutton 1999). Reducing these morbidities would enhance quality of life for these infants and benefit their families and communities (Saigal 2000).