Background

There is now an emerging body of information that suggests that some of the complications associated with extreme immaturity are potentiated by an excess of free radicals in infants who are intrinsically deficient in antioxidants, such as superoxide dismutase, catalase, and glutathione peroxidase. During hypoxia, metabolic alterations prime hypoxic cells to produce free oxygen radicals when subsequently exposed to oxygen. Such reperfusion injury, in addition to increasing the production of free oxygen radicals, is associated with other metabolic changes that may produce long-lasting harmful effects. Low plasma antioxidant activity at birth in premature infants may be an independent risk factor for mortality. Pulmonary oxygen toxicity, through the generation of reactive oxygen/nitrogen species in excess of antioxidant defenses, may be a contributor to the development of bronchopulmonary dysplasia (BPD). Immaturity is a factor explaining free radical–mediated pulmonary protein oxidation in premature newborns, and oxidation of proteins is related to the development of chronic lung disease. It has been reported that oxygen toxicity can also increase the risk of retinopathy of prematurity (ROP), mortality, periventricular leukomalacia, and cerebral palsy. However, oxygen restriction was also associated with an increased risk of death and cerebral palsy.

A meta-analysis of air versus 100% oxygen for newborn resuscitation that included four randomized trials revealed a decreased rate of death in the group resuscitated with room air (relative risk [RR] 0.71 [95% confidence interval (CI) 0.54−0.94], risk difference [RD] −0.05 [95% CI −0.08 to −0.01]). However, longer durations of differential oxygen exposures had not been tested in randomized controlled trials in infants before the recent oxygen saturation (Sp o ₂ ) targeting trials.

For long-term use in infants, the American Academy of Pediatrics (AAP) recommended targeting oxygen saturation (Sp o ₂ ) between 85% and 95% or partial pressure of arterial oxygen of 50 to 80 mm Hg based on opinion as data were very limited. Before the recent Sp o ₂ targeting trials, there had been limited data from observational studies that suggested that targeting oxygen saturations below 90% may improve outcomes.

Observational Studies of Oxygenation Targeting

Tin et al. reviewed outcomes for infants admitted to neonatal intensive care units (NICUs) in northern England from 1990 to 1994 with policies to maintain either lower (70%–90%) or higher Sp o ₂ ranges (88%–98%). They reported that infants managed with lower Sp o ₂ targets (70%–90%) developed ROP less often (6.2% vs. 27.2%), underwent a shorter duration of ventilation (14 days vs. 31), were less likely to be receiving oxygen at 36 weeks (18% vs. 46%), and were less likely to have a weight below the third centile at discharge (17% vs. 45%) than infants managed in NICUs with the higher Sp o ₂ targets (88%–98%). Very importantly, mortality and cerebral palsy did not differ by Sp o ₂ target groups. On follow-up at 10 years of age, fewer children cared for in NICUs with the lower Sp o ₂ targets had cognitive disability compared with those treated in NICUs with higher Sp o ₂ targets (23% vs. 35%). In addition, the mean intelligence quotient (IQ) of children was 8 points higher in those managed in the lower Sp o ₂ target NICUs. There were also more children with very low scores on the Vineland Adaptive Behavior Scales in the higher compared with the lower Sp o ₂ target group (34% vs. 20%). At 10 years, there were 5 blind children among 64 survivors in the higher Sp o ₂ target group versus none of 60 in the lower Sp o ₂ target group. These results provided reassurance that restrictive oxygen therapy in infants of less than 28 weeks’ gestation was safe and effective in improving outcomes and that lower Sp o ₂ targeting may reduce adverse outcomes such as neurodevelopmental impairment and blindness.

Another observational study designed as a before-and-after study reported ROP and mortality outcomes in infants managed in the same unit when Sp o ₂ targets were decreased to 83% to 93%. In this study, it was found that the incidence of ROP stages 3 to 4 decreased consistently in a 5-year period from 12.5% to 2.5%, and the need for laser treatment decreased from 4.5% to 0% following the institution of a detailed oxygen management policy that included strict guidelines for increasing and weaning the fraction of inspired oxygen and the monitoring of Sp o ₂ . Annual survival rates showed a trend toward improvement for all infants, especially for those with birth weights of 500 to 749 g.

A prospective, multicountry observational study by Hagadorn et al. was designed to measure achieved Sp o ₂ levels in extremely preterm infants. The participating NICUs reported their targeted Sp o ₂ ranges and continuous recordings of Sp o ₂ were collected. This study showed that target saturations differed markedly by center in a range from 83% to 98% and that targeted Sp o ₂ was typically achieved less than 50% of the time.

Using transcutaneous oxygen monitoring, Bancalari and collaborators were able to show that infants who received continuous monitoring had a similar incidence of ROP compared to infants who were monitored by intermittent sampling. However, for the subgroup of infants with birth weights below 1100 g, there was a decreased incidence of ROP using transcutaneous arterial oxygen targets of 50 to 80 mm Hg compared with infants managed with intermittent blood gas sampling.

Two randomized controlled trials of oxygen saturation targeting have been conducted during the postneonatal period to test oxygen saturation targets above 95%. The Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP) trial included 649 infants who were born at a mean of 25 weeks and were 35 weeks at enrollment. Targeting oxygen saturations above 95% slightly reduced the number of infants who went on to have severe disease requiring retinal surgery. However, targeting oxygen saturations above 95% increased the proportion of infants who required prolonged oxygen supplementation and diuretics. The Benefits of Oxygen Saturation Targeting (BOOST) trial was a double-blind, randomized controlled trial that compared an oxygen saturation target of 91% to 94% versus a target of 95% to 98% in 358 infants less than 30 weeks at birth who required oxygen at 32 weeks postmenstrual age. Oxygen growth and development, which were the main outcomes, were not improved with the higher oxygen saturation targeting. Furthermore, and consistent with the STOP-ROP trial results, targeting higher oxygen saturations increased the use of postnatal steroids and diuretics and resulted in more readmissions and more pulmonary-related deaths. Given this evidence, there have not been more trials testing oxygen saturation targets above 95%.

Data from several observational studies indicated wide ranges of practices and suggested the safety and benefits of targeting transcutaneous oxygen of 50 to 80 mm Hg or Sp o ₂ below 90%. Many experts in the field recommended that randomized clinical trials were needed to test different oxygenation targets. As continuous Sp o ₂ measurements had become the standard of care, it made more sense to test continuous Sp o ₂ targets rather than continuous transcutaneous partial pressure of oxygen targets or intermittent blood gas targets. One of the giants in neonatology, Dr. Bill Silverman, wrote in 2004 “Recent observations have suggested that oxygen-saturation targets used for many decades in the treatment of extremely low gestational age neonates (<28 weeks) have been too high.” Silverman added “I am encouraged to learn that these disturbing findings have now inspired efforts to organize an international RCT in the hope of finding an optimum range of oxygenation to minimize the risks of four competing outcomes: mortality, retinopathy, cerebral palsy, and chronic lung disease.” Indeed, five randomized controlled trials were soon initiated in the United States, Canada (whose studies included many other countries), the United Kingdom, Australia, and New Zealand.

The Support Trial

The first trial of Sp o ₂ targeting starting soon after birth—the Surfactant, Positive Pressure, and Pulse Oximetry Trial (SUPPORT)—was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network clinical centers. SUPPORT was designed to compare the effects of a lower Sp o ₂ target (85%–89%) and a higher Sp o ₂ target (91%–95%). Infants of 24 to 27 weeks’ gestation were enrolled prenatally or by 2 hours after birth. Blinding was maintained with the use of electronically altered pulse oximeters (Masimo Radical Co-Oximeter, Irvine, CA) that displayed saturation levels of 88% to 92% as the target range for both groups, with a maximum variation of 3%. Targeting of arterial oxygen saturation was continued until 36 weeks of postmenstrual age or until the infant was breathing ambient air and had not received ventilator support or continuous positive airway pressure for more than 72 hours. The main outcome measures were severe ROP or death (short term) and neurodevelopmental impairment or death at 24 months corrected age (longer term). A total of 1316 infants were enrolled. The primary outcome did not differ between the lower and higher Sp o ₂ intervention groups (28.3% and 32.1%, respectively; RR with lower Sp o ₂ target group 0.90, 95% CI 0.76–1.06, P = .21), but unexpectedly there was a lower mortality rate in the infants in the higher Sp o ₂ target group (16.2% vs. 19.9%, P = .04). Severe ROP occurred less often in the 85% to 89% Sp o ₂ target group (8.6% vs. 17.9%, P < .001). There were no significant differences in the rate of BPD, neurodevelopmental impairment, blindness, other ophthalmologic outcomes, patent ductus arteriosus, intracranial hemorrhage, or other major outcome measures.

Other Randomized Controlled Trials

There was an international effort to conduct other randomized controlled trials similar to the SUPPORT trial. A collaboration to conduct an individual participant data prospective meta-analysis—the Neonatal Oxygen Prospective Meta-Analysis (NeOProM) Collaboration—was established and the protocol for this collaboration was published. This collaboration resulted in four other funded grant applications that led to completion of the BOOST UK and BOOST Australian trials, the Canadian Oxygen Trial (COT), and the New Zealand BOOST trial. These four trials were very similar to SUPPORT because the protocols were shared prospectively. The similar design optimized the planned individual participant data meta-analysis.

The four trials were conducted as planned, but the BOOST UK and BOOST Australia trials stopped enrollment early because of an unexpected higher mortality rate in the higher Sp o ₂ target groups. For brevity, the results of these trials are presented together with the SUPPORT results as a Cochrane meta-analysis has just been published.