Results from published systematic reviews and meta-analyses also have been equivocal, with statistically mixed results of various outcome measures. In a 2009 Cochrane systematic review of 5 studies published before 2005, Askie et al48 concluded that a policy of unrestricted or unmonitored oxygen therapy has potential harms, particularly ROP, without clear benefits compared with a restricted oxygen use protocol. In a 2014 meta-analysis of the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT), 3 Benefits of Oxygen Saturation Targeting (BOOST) studies, and Canadian Oxygen Trial (COT), Saugstad and Aune49 found that lower oxygen saturation target levels were associated with more deaths and more incidences of necrotizing enterocolitis, but less ROP, than higher target levels. Manja et al50 also reviewed these 5 studies and found that the lower oxygen saturation target group had higher mortality before hospital discharge and a higher incidence of necrotizing enterocolitis than the higher oxygen saturation group, but no difference was observed for neurodevelopmental outcomes, ROP, or hearing loss. However, significant outcomes were associated with a low level of confidence; thus, the investigators concluded that the optimal target oxygen saturation in extremely preterm infants remains uncertain.50
The most recent pooled analysis included data from 2 BOOST II studies (correcting an oximeter calibration–algorithm artifact); investigators found that an oxygen saturation target range of 85% to 89% was associated with a significant increase in risk of the combined outcome of death or disability and the outcome of death alone compared with a higher target range of 91% to 95%.51 Variations in study populations across the 5 major studies of the Neonatal Oxygen Prospective Meta-analysis Collaboration, of which the BOOST II studies were a part, may account for differences in mortality rates51 and therefore limit the ability to determine statistical significance consistently for these differences. Moreover, achieved versus intended oxygen saturation was highly variable in these studies and may have influenced results.52 However, taken together, these 5 studies suggest that lower oxygen saturation levels may increase the risk of death; thus, targeting oxygen saturation at 91% to 95% may be safer.51,52 These higher target ranges must be monitored closely and should not exceed 95% at the risk of developing disorders associated with oxidative stress.3,52 Importantly, the oxygen saturation target range may vary with advancing gestational age and postnatal age.46
In 2003, the Cedars-Sinai Medical Center and UCLA School of Medicine published a protocol for the management of supplemental oxygen use with oxygen saturation target levels of 85% to 93% and setting low and high alarms, respectively.30 Implementation of this protocol has been associated with a significantly shorter length of hospital stay, decreased need for supplemental oxygen and steroids for chronic lung disease, and a lower rate of ROP in very low birth-weight infants.30,53,54 In another study targeting oxygen saturation between 88% and 92% with alarm limits of 85% and 95%, respectively, the incidence of chronic lung disease was significantly reduced (P = .001) and fewer infants were discharged from the hospital with oxygen therapy than those with less restrictive oxygen protocols that were previously used.55
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