The oxygen dilemma: oxygen saturation targets in preterm infants

Controversy about the optimal oxygenation of premature infants has existed since the unrestricted use of supplemental oxygen caused an epidemic of retinopathy of prematurity (ROP) in American nurseries in the 1940s and 1950s. As the understanding of oxygen toxicity in preterm infants developed, avoiding hyperoxia and hypoxic events became a choice between two evils. This persisted when continuous monitoring with pulse oximetry became standard care in neonatal intensive care units during the 1990s. Evidence from controlled trials on optimal oxygenation has been lacking. The 2007 American and European consensus guidelines were mainly based on observational studies, and they recommended rather wide peripheral capillary oxygen saturation (SpO2) target ranges for immature infants during the first weeks after birth. In Europe, this was <95%, with no lower limit, and the American Academy of Pediatrics (AAP) recommended 85–95% 1, 2. The European targets were adjusted to 85–93% in 2010 and 90–95% in 2013 3. These developments reflected data from five randomised multicentre trials, which provided new evidence about how different saturation targets affected extremely preterm infants. They had similar protocols and compared the outcomes of infants born before 28 weeks of gestation who were randomised to lower (85–89%) and higher (90–95%) SpO2 targets. Pulse oximeters were programmed to display saturations either 3% below or 3% above the actual values in order to mask the intervention to caregivers. Individual patient data from 4965 participants in five trials were included in the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration and summarised in several systematic reviews. Meta-analyses showed a significant increase in mortality in the low SpO2 target group (19.9% versus 17.1%) with a relative risk (RR) of 1.17 and 95% confidence interval (95% CI) of 1.04–1.13. The lower SpO2 target range was also associated with an increased risk of necrotising enterocolitis (RR 1.33, 95% CI 1.10–1.61), whereas ROP treatment was significantly lower in the higher SpO2 target group than in the lower one (10.9% versus 14.9%, RR 0.74, 95% CI 0.63–0.86). There were no significant differences between the groups regarding cerebral palsy, severe visual impairment, deafness, bronchopulmonary dysplasia or the combined outcome of death or major neurodevelopmental impairment at a corrected age of 18–24 months 4. In this issue of Acta Paediatrica, Klevebro et al 5 report the results from a retrospective study carried out in Stockholm before and after the 2013 European consensus guidelines were integrated into local practice at the Karolinska Institutet. The study comprised 399 infants born between 23 and 30 weeks of gestation who received supplemental oxygen during the first three weeks of life. The 98 infants treated before the guidelines received the lower SpO2 target of 88–92%, with alarm limits of 85–95%. The 301 treated after the guidelines received the higher SpO2 target of 90–95%, with alarm limits of 89–96%. SpO2 was monitored continuously, and the values were extracted from the patient monitoring system. The mean difference in SpO2 between the low and high groups was only 1.3% (91.1% versus 92.4%). However, following the implementation of the new guidelines, the SpO2 was within the prescribed range in the high target group more frequently (51% versus 30%), whereas the time with hyperoxia (SpO2 >95%) increased from 20 to 28% and time with hypoxaemia (SpO2 <80%) significantly decreased from 10 to 7%. No difference in ROP or mortality was found. Klevebro et al 5 provide an important evaluation of the implementation of the 2013 oxygen saturation guidelines. The significantly higher adherence to the targeted SpO2 range in the post-implementation period, despite the small mean difference of 1.3% in SpO2 between the two periods, is probably explained by more narrow alarm limits. However, the authors state that since the higher saturation target and tighter alarm limits were introduced simultaneously, it is not possible to separate their effects. The 51% adherence was similar to previous randomised trials. Maintaining SpO2 within a narrow target range through multiple manual adjustments is time-consuming and challenging. A qualitative study from The Canadian Oxygen Trial reported that nurse education, prompt responses to alarms and a favourable patient-to-staff ratio were the most important determinants of good compliance with SpO2 alarm limits 6. In a busy neonatal intensive care unit, an alarm limit that is too narrow, leading to a large number of false alarms, must be weighed against a limit that is too wide, leading to poor adherence to SpO2 targets. Servo-controlled oxygen algorithms are a promising innovation that have been reported to improve SpO2 targeting compared with manual control. However, no significant beneficial effects on outcome have been demonstrated 7. Klevebro et al 5 found that the higher SpO2 target range resulted in less time with hypoxaemia. The late effects of intermittent hypoxaemia were addressed in a post hoc analysis by the Canadian Oxygen Trial and were associated with an increased risk of late death or disability at 18 months of age, suggesting that further preventative research is needed 8. Implementing the higher oxygen saturation range targets in the 2013 European guidelines might lead to higher rates of ROP in many centres. Klevebro et al's 5 study was underpowered to examine the effects on mortality and ROP, but a previous single-centre study from Australia indicated significantly higher rates of ROP after implementing a higher SpO2 target range 9. This emphasises the importance of performing large randomised studies with sufficient power to find the optimal oxygenation level for immature infants. As ROP strongly correlates to gestational age, increased survival of the most immature infants will probably lead to more ROP over time. In fact, increased survival rates and higher rates of severe ROP among survivors were reported in England from 1995 to 2006 and from 1993 to 2012 in the United States 10, 11.These findings raise concerns about a risk of increased incidence of blindness due to severe ROP in the future. Interestingly, despite the significantly increased risk of treated ROP in the high SpO2 target arm of the NeOProM studies, the risk of severe visual impairment was not different between the two treatment groups. This finding probably reflects the efficiency of modern treatment of severe ROP. Although ophthalmological problems continue to account for a high proportion of long-term sequelae of prematurity, blindness is rare today and has been reported in 1–2% of surviving infants 12. However, introducing the new oxygenation guidelines in a low-resource setting without modern ophthalmological treatment will probably lead to higher rates of visual and neurodevelopmental disability. The NeOProM Collaboration provides the best evidence about oxygen saturation targets in extremely preterm infants to date and resulted in further recommendations after 2013. In 2016, the targets were further narrowed to 90–94% in Europe and 90–95% by the AAP’s Committees on foetuses and newborn infants 13, 14. The AAP highlights that the ideal oxygen saturation target for extremely low birthweight infants remains unknown, and is likely to be patient specific and dynamic and depends on various factors, including gestational age, chronologic age, underlying disease and transfusion status. In 2016, upper alarm limits of 95% were suggested by both European and AAP guidelines for the first time. A lower limit of 89% is recommended in European guidelines, with no definite lower limit recommended by the AAP. The AAP states that the lower limit needs to extend somewhat below the lower target, as it must take into account practical and clinical considerations and the steepness of the oxygen saturation curve at lower saturations. This shows that the European and American guidelines have developed in a similar way and with smaller variations. Klevebro et al's 5 retrospective study was underpowered to answer whether the most novel recommended saturation target limits may increase ROP, but decrease mortality and necrotising enterocolitis in immature infants. Future randomised studies should answer three key questions. Should the SpO2 targets and alarm limits be kept constant throughout the observation period or would an adjustment for increasing maturity reduce complications? Should the most immature infants, for instance those born at <26 weeks, be treated the same as those born at 28 weeks GA? What can be done to address the lack of data on optimal oxygenation for babies born at more than 27 weeks? Perhaps answering such questions may help us individualise and optimise oxygenation levels for preterm infants, while further reducing complications and the oxygen dilemma. None. None.

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