Current Recommendations and Practice of Oxygen Therapy in Preterm Infants

C u r ren t R e c o m m e n d a t i o n s a n d P r a c t i c e o f Ox y g e n T h e r a p y in Pret e r m I n f a n t s William Tarnow-Mordi, Adrienne Kirby, MSc BA, MB BChir, MRCP (UK), DCH*, KEYWORDS  Oxygen  Oxygenation  Oximetry  Infant mortality  Necrotizing enterocolitis  Retinopathy of prematurity  Extremely premature infant KEY POINTS  Because low-oxygen saturation targets increased mortality in extremely preterm infants, all guidelines since 2011, except one, have recommended targeting oxygen saturation ranges of 91% to 95% or 90% to 95%, or avoiding 85% to 89%.  The quality of the evidence that the low target increased mortality has been rated as “high,” “moderate,” or “low” despite the low heterogeneity between randomized trials of oxygen saturation targeting, suggesting key differences in interpreting the GRADE guidelines.  International surveys in 2015 and 2016 showed that oxygen saturation target ranges had increased to levels that are more consistent with the evidence.  Randomized controlled trials on oxygen saturation targeting have excluded moderately and late preterm infants. This is a major evidence gap.  Systematic reviews, guidelines, and consensus statements without biostatisticians or epidemiologists as coauthors should be considered potentially problematic. INTRODUCTION Authors of systematic reviews, editorial commentaries, opinions, consensus statements, and guidelines render a valuable service in summarizing the best available evidence for clinical practice. Similarly, those who undertake periodic questionnaire surveys reveal whether this appraisal of the evidence subsequently impacts clinical practice. After 2 systematic reviews, which were published in 2017 and 2018,1,2 had Disclosure Statement: W. Tarnow-Mordi and A. Kirby were Chief Investigators of the BOOST II Study, funded by the Australian National Health and Medical Research Council and coinvestigators of the NeOPrOM Collaboration. NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia * Corresponding author. E-mail addresses: williamtm@med.usyd.edu.au; wotarnowmordi@gmail.com Clin Perinatol 46 (2019) 621–636 https://doi.org/10.1016/j.clp.2019.05.015 0095-5108/19/ª 2019 Elsevier Inc. All rights reserved. perinatology.theclinics.com 622 Tarnow-Mordi & Kirby assessed the 5 Neonatal Oxygen Prospective Meta-analysis (NeOProM) trials of low(85%–89%) versus high- (91%–95%) oxygen saturation target ranges in infants of less than 28 weeks’ gestation,3–7 the authors evaluated published (i) recommendations for oxygen-saturation target ranges in these infants during oxygen therapy after admission to the neonatal unit and (ii) surveys of practice. The GRADE Working Group Guidelines Several systematic reviews, commentaries, and consensus statements have cited the GRADE guidelines8–10 in assessing (a) the quality of evidence and (b) the strength of recommendations made. The 4 grades of evidence in the GRADE guidelines are high quality (indicating that further research is very unlikely to change the confidence in the estimate of effect), moderate quality (further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate), low quality (further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate), and very low quality (very uncertain about the estimate). Evidence from observational studies is initially rated as of low quality, but ratings can be modified upward, while evidence from randomized studies is initially rated as of high quality, but ratings can be modified downward. After assessing the quality of evidence, GRADE gives criteria to rate recommendations for practice as “strong” or “weak.”11 The GRADE process begins with a Health Care Question (Patient Intervention, Comparator, Outcome), progresses through systematic reviews of all evidence addressing that question, rates the quality of evidence of each outcome across studies and overall, and then rates the strength of the resulting recommendations, as summarized in Fig. 1. OXYGEN SATURATION TARGETS IN INFANTS LESS THAN 28 WEEKS’ GESTATION Methods Search strategy The authors searched PubMed for systematic reviews, editorial commentaries, opinions, consensus statements, and guidelines on oxygen therapy in infants less than 28 weeks’ gestation, excluding (i) reports of individual randomized controlled trials (RCTs) of low- versus high-oxygen saturation targets, (ii) guidelines focusing on a single measure of outcome, for example, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and (iii) systematic reviews or commentaries on oxygen targeting during resuscitation or delivery room care. Further relevant articles were obtained from the reference lists of publications identified as above. The search was limited to the period since the publication in 2010 of SUPPORT,3 the first of the NeOProM trials.12 The search terms were “((clinical practice guidelines) AND preterm AND oxygen) NOT resuscitation,” which yielded 18 hits and “systematic review AND preterm AND oxygen NOT resuscitation,” which yielded 90 hits. Guidelines, systematic reviews, narrative reviews, commentaries, opinions, and consensus statements were selected from among these 108 hits. This search strategy yielded 23 publications (Table 1).1,2,13–33 The authors also searched CINAHL using the terms (“Infant, Premature”) AND (“Practice Guidelines”), which yielded 28 hits, none of which were relevant. These strategies also yielded 2 surveys of clinical practice, one conducted between November 2015 and February 2016 in 193 European neonatal intensive care units (NICUs),34 and another among representatives of 329/390 NICUs of the International Network for Evaluating Outcomes in Neonates (iNeo), conducted in 2015.35 Practice of Oxygen Therapy in Preterm Infants Fig. 1. Schematic view of GRADE’s process for developing recommendations. a Also labeled “conditional” or “discretionary”. PICO, patient, intervention, comparator, outcome. (From Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383–94; with permission.) Results Recommendations for practice The authors found 2 consensus guidelines,19,29 a clinical report from the Committee on Fetus and Newborn of the American Academy of Pediatrics (AAP),26 5 systematic reviews,1,2,20,22,28 and 13 commentaries or opinions (see Table 1). European Consensus guidelines and American Academy of Pediatrics Clinical Report In 2016, the European Consensus Guidelines on Management of Respiratory Distress Syndrome,29 in an update of its earlier consensus statement,19 suggested an oxygen saturation target of 90% to 94% for all preterm infants less than 28 weeks’ gestation. Using the GRADE guidelines,8 the European Consensus group assessed the overall quality of evidence for this recommendation overall, rather than for specific outcomes, as “moderate” and the strength of this recommendation as “weak.” In 2016, the AAP Committee on Fetus and Newborn26 concluded that an oxygen saturation target range greater than 89% may be safer, at least for some infants. 623 624 Tarnow-Mordi & Kirby Table 1 Recommendations for oxygen saturation target ranges and alarm limits First Author, Year Type of Publication Recommended Target Range Quality of Evidence (Strength of Recommendation) Saugstad et al,13 2011 Commentary >89% - Bashambu et al,14 2012 Narrative review >89% - Askie,15 2013 Opinion >90% - Polin & Bateman16 2013 Commentary 90%–95% - Bancalari & Claure,17 2013 Commentary 90%–95% - Stenson,18 2013 Opinion 90–95 - Sweet et al,19 2013 Consensus statement 90%–95% Moderate Saugstad & Aune,20 2014 Systematic review 90%–95% - Schmidt et al,21 2014 Commentary 85%–88% to 93%–94%a 89%–90% to 95%b - Systematic review - Lowc Synnes & Miller,23 2015 Commentary 85%–95% - Isaacs24 2016 Commentary 91%–95% - Stenson25 2016 Commentary 90%–95% - Cummings et al,26 2016 Committee clinical report 90% to 95%d,e - Manja et al, 22 2015 Deschmann & Norman,27 2017 Commentary 91%–95% Manja,28 2017 Systematic review 91%–95%e Sweet, 29 2017 Askie,1 2017 Consensus statement 90%–94% Systematic review - e Moderatec Moderate (weak) Highc Kayton,32 2018 Commentary 91%–95% - Askie et al,2 2018 Systematic review - - Bizzarro,30 2018 Commentary 91%–95% - Einhorn,33 2018 Commentary 91%–95% - Stenson & Saugstad,31 2018 Commentary 91–95e - Practice of Oxygen Therapy in Preterm Infants Bold indicates systematic review; italics indicates an outlier commentary which recommends 85-95% in contrast to other commentaries which recommend ranges above 89%. a e.g. alarm limits in hospitals with low rates of mortality and necrotizing enterocolitis but high rates of severe ROP. b e.g. alarm limits in hospitals with low rates of severe ROP, but high rates of mortality and necrotizing enterocolitis. c For effect on mortality. d 90 to 95% may be safer than 85% to 89% in some infants. e Lower alarm limit will generally need to extend somewhat below the lower target. 625 626 Tarnow-Mordi & Kirby Although the disproportionately high rate of mortality in small-for-gestational-age infants in the low-target group was discussed, the committee did not define those infants in whom it considered a higher saturation target safer. The AAP Committee on Fetus and Newborn did not apply the GRADE guidelines. Systematic reviews In 2014, Saugstad and Aune20 published a systematic review and meta-analysis on infants less than 28 weeks’ gestation reported in the 5 NeOProM trials. They reported no difference in death or disability up to 24 months corrected gestational age in 2463 infants in SUPPORT3 and COT,5 the 2 trials that had reported this outcome. However, all 5 trials reported an increased relative risk (RR) for mortality at discharge or follow-up (4884 infants; RR 1.41; 95% confidence interval [CI] 1.14–1.74) and for necrotizing enterocolitis (NEC) (4929 infants; RR 1.25, 95% CI 1.05–1.49). Results were inconclusive for ROP, BPD, brain injury, and patent ductus arteriosus. They recommended adoption of an oxygen saturation target range of 90% to 95% until 36 weeks’ gestation but did not use the GRADE guidelines to assess the quality of evidence or strength of this recommendation. In 2015, Manja and colleagues22 published a systematic review in 4929 infants reported in the 5 NeoProM trials, which was the first to use the GRADE guidelines8 to assess the quality of evidence for each outcome. It reported (i) no effect for death or disability up to 24 months corrected gestational age in 3 trials (2716 infants; RR 1.02, 95% CI 0.94–1.14: quality of evidence downgraded to moderate8); (ii) increased hospital mortality in the low-target group across 4 trials (3757 infants; RR 1.18, 95% CI 1.03–1.36: quality of evidence downgraded to low8 because, among other reasons, the separation in oxygen saturation achieved between low- and high-target groups was less than planned); (iii) that the low target increased NEC in 5 trials (4929 infants; RR 1.24%, 95% 1.05–1.47; quality of evidence downgraded to moderate); (iv) no effect for severe ROP in 5 trials (4066 infants; RR 0.72, 95% CI 0.5–1.04; quality of evidence downgraded to low8 because of unexplained heterogeneity); and (v) no effect for BPD, neurodevelopmental outcomes at 18 to 24 months, and hearing loss (quality of evidence downgraded to moderate8). In 2017, Manja and colleagues28 published a systematic review of RCTs evaluating the effect of lower (85%–89%) versus higher (91%–95%) pulse oxygen saturation (SpO2) target on mortality and neurodevelopmental impairment at 18 to 24 months.28 They concluded that the risks associated with restricting the upper SpO2 target limit to 89% outweighed the benefits. The quality of evidence was moderate. They speculated that a wider target range (lower alarm limit, 89%, and upper alarm limit, 96%) might increase time spent within the 91% to 95% range. In 2017, Askie and colleagues1 published a Cochrane Review of the effects of targeting lower versus higher arterial oxygen saturations on death or disability in preterm infants, based on the 5 NeOProM trials, in a total of 4965 infants less than 28 weeks’ gestation. They applied the GRADE guidelines to assess the quality of evidence for estimates of the effect of the low-target range on individual outcomes. Their assessments of the quality of evidence for these outcomes have been summarized alongside the assessments of Manja and colleagues22 in Table 2. In 2018, Askie and colleagues2 published the results of the previously planned12 prospective individual patient data meta-analysis of the effects of targeting 85% to 89% versus 91% to 95% oxygen saturation in all 4965 infants less than 28 weeks’ gestation in the 5 NeOProM Collaboration trials. This publication2 (which did not apply the GRADE guidelines12) and the Cochrane Review by Askie and colleagues1 suggest that for every 1000 infants, targeting low- versus high-oxygen saturation made no difference in death or major disability up to 18 to 24 months, nor in major disability, Practice of Oxygen Therapy in Preterm Infants Table 2 Observed effects of the low-target range 85% to 89% on individual outcomes in 2 systematic reviews of 5 trials, with quality of evidence assessed by GRADE Observed Effect of 85%–89% Target Quality of Evidence on This Outcome in as Assessed in Manja et al,22 2015 Manja et al,22 2015 Observed Effect of 85%–89% Target on This Outcome in Askie et al,1 2017 Quality of Evidence as Assessed in Askie et al,1 2017 Death or disability at 24 mo No effect Moderate No effect High Hospital death Increased Low Increased High Moderate No effect High Outcome Disability at No effect 18–24 mo NEC Moderate Increased High Treated ROP No effect Increased Low No effect Moderate Hearing loss No effect Moderate No effect Not assessed Blindness Moderate No effect Not assessed No effect including blindness, but led to 28 more deaths, 22 more cases of NEC, and 42 fewer infants being treated for ROP.1,2,36 Table 3 presents the authors’ reasons for uprating the Quality of Evidence that the low target increases mortality in the NeOProM trials in 2 systematic reviews using GRADE from “low”22 to “high.”1 SURVEYS OF CLINICAL PRACTICE IN OXYGEN TARGETING AMONG INFANTS LESS THAN 28 WEEKS’ GESTATION In a Web-based survey among representatives of 390 NICUs of the International Network for Evaluating Outcomes in Neonates (iNeo) conducted in 2015, responses were received from 329 (84%).35 Of these, 60% had recently made changes to their upper and lower SpO2 target limits, with the median value of the target range set higher than previously by 2% to 3% in 8 of 10 networks. In a similar survey of 193 European NICUs conducted in 2015 and 2016,34 there was considerable variation in practice. The most frequently targeted oxygen-saturation ranges were 90% to 95% (28%), 88% to 95% (12%), 90% to 94% (5%), and 91% to 95% (5%), reflecting the most commonly recommended target ranges shown in Table 1. A total of 156 NICUs (81%) had recently changed their oxygen saturation target limits. The median values for the oxygen-saturation ranges in clinical practice had increased by between 3% and 5% within the last 10 years. Neither survey determined current practice in setting alarm limits nor in oxygen saturation targeting for preterm infants of 30 to 36 weeks’ gestation. Discussion All 5 systematic reviews of trials of oxygen saturation targeting for infants of less than 28 weeks’ gestation that were identified since 2010 concluded that the low target 85% to 89% increased mortality.1,2,20,22,28 Table 1 shows notable uniformity in recommendations for practice. Of 16 guidelines, commentaries, or opinions published since SUPPORT in 2010 (see Table 1), 15 recommended targeting a range greater than 627 628 Tarnow-Mordi & Kirby Table 3 Contrasting interpretations of the quality of evidence that the low target increased mortality in randomized controlled trials of oxygen saturation targets in infants less than 28 wk using GRADE8 Initial Reason for Downgrading Quality of Evidence22 Our Interpretation of the Effect on Quality of Evidence Reinterpretation Using the GRADE Guidelines 1. Separation of achieved SpO2 values was less than planned Despite less than expected separation, mortality effects were still observed. This confounding is likely to have reduced the effect (see Fig. 18) 2. The oximeter algorithm was revised during enrollment to 3 trials5,7 The revised algorithm improved Rating should be separation in oxygen modified upward saturation36 and thus study power. The original algorithm reduced separation (see Fig. 18), thus underestimating the average estimate of effect36 Rating should be modified upward 3. Mortality in infants on the revised The BOOST II protocols specified a Rating should be algorithm was not a difference in a major endpoint modified upward prespecified outcome; yet 2 of >3 standard errors or >3 BOOST II trials7,37 were stopped standard deviations (equivalent to P<.0027) to justify early early because of an increase in stopping. After SUPPORT this outcome showed excess mortality,3 the BOOST II trials7,37 were stopped early because of a highly significant increase in pooled mortality in infants on revised oximeters (RR 1.65; P 5 .0003)38 4. Only 43,6,37 of 5 trials reported hospital death The estimates of effect on hospital death in these 4 trials demonstrate low to moderate heterogeneity39 (c2 4.76, P 5 .19; I2 5 37%) No effect on rating Other issues 5. Effects on mortality using revised The mortality risk for low- vs high- Rating should be vs original oximeters; among target infants was greater in modified upward infants on revised oximeters, those using revised vs original low-target infants had oximeters.8 This, and the consistently higher mortality finding that targeting was than high-target infants, with more accurate in infants using (a) statistically significant revised oximeters,36 is likely to interactions in 3 meta-analyses have caused the average effect of mortality in low- vs highof the low target on mortality target infants stratified by use in infants on original oximeters of original vs revised oximeters to have been underestimated, (P 5 .00638; P 5 .031,20; as in 1 above (see Fig. 18) P 5 .0422) (but interactions were unreported in 2 metaanalyses20,22); (b) Infants using revised oximeters spent more time in their assigned target ranges than those on original oximeters36 (continued on next page) Practice of Oxygen Therapy in Preterm Infants Table 3 (continued ) Initial Reason for Downgrading Quality of Evidence22 Reinterpretation Using the GRADE Guidelines Our Interpretation of the Effect on Quality of Evidence Shows high quality 6. What was the potential for biased None. Death was assessed assessment of mortality? without interobserver variation or bias 7. Was there loss to follow-up in ascertainment of mortality? No. 100% ascertainment of death Shows high quality at 36 wk and before hospital discharge 8. Was the magnitude of the effect Yes. The low target shows a 38% Rating should be modified upward on mortality large? increase in RR of death in infants on revised oximeters (RR 1.38, 95% CI 1.13–1.68; P 5 .014)1 (see Fig. 18) 90% or avoiding the low-target range of 85% to 89%. The exception was an editorial commentary,23 which suggested that targeting an oxygen-saturation range between 85% and 95% remained acceptable. Two international surveys34,35 in approximately 500 neonatal units reported considerable variation in clinical practice, but documented recent increases of 2% to 5% in the median values for target oxygensaturation ranges. CONTRASTING INTERPRETATIONS OF CURRENT RANDOMIZED EVIDENCE The recommendation23 that an oxygen-saturation target range of 85% to 89% remained acceptable23 reflects a judgment in the systematic review of Manja and colleagues22 that the GRADE quality of evidence that the low target increased mortality was low. This conclusion merits reconsideration. Reviewers may legitimately disagree when interpreting quality of evidence using GRADE, which provides a transparent framework guiding the assessment process (see Fig. 1).8,9 Table 2 shows judgments from 2 systematic reviews1,22 about the quality of evidence for the effect of the low target on various outcomes. Table 3 outlines the present authors’ reasons for reinterpreting the quality of evidence for the effect of the low target on mortality as “high” rather than “low,” using GRADE. For example, a treatment effect for mortality was observed despite the confounding effect of achieving less separation between study arms in actual oxygen saturation than planned. This result supports an upward modification of the rating for quality (see Fig. 1). Neither the European Consensus Guidelines nor the AAP Guidance has been updated since these most recent data were published.1,2 Future recommendations may benefit from inviting coauthorship by colleagues with advanced biostatistic and epidemiologic expertise. Indeed, attempting to synthesise and interpret complex trial data without such expertise might be compared with attempting brain surgery without a neurosurgeon. Future international clinical surveys32–35 and other evidence36,40 are warranted, to assess the impact on practice of the final results of the NeOPrOM trials.1,2 Future practice may also be influenced by increasing attention to 5 questions: i. Did the pulse oximeters which were used in the NeOProM trials estimate hypoxemia with progressively wider limits of accuracy as true oxygen-saturation values (SaO2) decreased from 93% to 80%, as reported in 2012 by Rosychuk 629 630 Tarnow-Mordi & Kirby et al (Fig. 2)?41 Did the pulse oximeters expose substantially more infants in the lower-target group to values of oxygen tension less than 50 mm Hg (6.7 kPa).42 The study authors41 wrote, “The large sample size of each of these (NeOProM) trials and the planned meta-analysis should address the question of whether infants assigned to the lower range are at higher risk of low PaO2-induced pulmonary vasoconstriction, patent ductus arteriosus, abnormal neuro-developmental outcome, and potentially death. Our data may provide partial explanations if differences in short- or long-term outcomes are observed.”41 ii. Could targeting an untested intermediate oxygen-saturation range, such as 87 to 93%, increase mortality versus a higher range because current oximeters inadvertently permit increasingly disproportionate exposure to hypoxemia as true oxygen saturation decreases below 93%? (see Fig. 2).40,41 At present, the most rigorously evaluated evidence for policy is that targeting oxygen saturations of 91 to 95% is safer overall than targeting oxygen saturations of 85% to 89%.1,2,40 The most reliable evidence for an intermediate range will come from an adequately powered RCT of two pre-specified target ranges, defined by pre-specified alarm settings. iii. Will future practice reflect recent analyses showing that infants with revised oximeters in the Australian and UK Benefits of Oxygen Saturation Targeting-II (BOOST II) trials spent longer in their planned pulse oximeter saturation target ranges than infants with the original oximeters (P<0.001)?36 There was no difference in separation of median oxygen saturation between infants with original vs revised oximeters,43 but the increased targeting accuracy in the low-target range Fig. 2. Proportions of SpO2 values that are 3% of the corresponding SaO2 value are plotted. The numbers above the x-axis on the graph denote the number of measurements at each value of SaO2, i.e. a total of 1,620 measurements. There is a highly significant difference in the proportions of measurements in which SpO2 is within  3% of the corresponding SaO2 value for values of SaO2 of 92% versus values of SaO2 >92% (Chi squared >63, p<0.0001). Further analyses adjusted for clustering by infant will be valuable. (From Rosychuk RJ, Hudson-Mason A, Eklund D, Lacaze-Masmonteil T. Discrepancies between arterial oxygen saturation and functional oxygen saturation measured with pulse oximetry in very preterm infants. Neonatology 2012;101:14–9; with permission.) Table 4 Sample sizes to show 10% or 20% reductions in relative risk of mortality or disability Total Sample to Show Effect in a 2-Arm Comparison with 90% Power, 2P 5 .05 and Nonadherence to Protocol Due to: Relative Risk Reduction (1 L RR) Number Needed to Benefit or Harm (100/D) 0% Crossover in Each Group (Perfect Adherence to Protocol) 5% Crossover in Each Group (Total 10% Crossover) 10% Crossover in Each Group (Total 20% Crossover) 16 4 0.8 0.2 25 3868 4776 6044 18 2 0.9 0.1 50 16,166 19,960 25,260 10 8 2 0.8 0.2 50 8598 10,616 13,436 10 9 1 0.9 0.1 100 36,136 44,164 56,464 Event Rate in Treatment Group (T), % 20 20 Data from Sealed envelope. Trial sample size calculator. Available at: https://www.sealedenvelope.com/power/. Accessed 24 Jan 2018. Practice of Oxygen Therapy in Preterm Infants Risk Difference (C L T 5 D), % Relative Risk or Risk Ratio (RR 5 T/C) Event Rate in Control Group (C), % 631 632 Tarnow-Mordi & Kirby with revised oximeters36 may explain the larger mortality difference between lowand high-target infants with revised oximeters. It also suggests that average treatment effects in the BOOST II trials are underestimates, as they include data from infants on the original oximeters.36 iv. Should future clinical policy be based on observational studies? No. David Sackett, an early advocate of Evidence-Based Medicine, stated “If you’re scanning an article about therapy and it is not a randomized trial, why on earth are you wasting your time?”44 Two major threats to the validity of therapeutic comparisons are random error and systematic bias. Randomization is the most reliable way to protect therapeutic comparisons from systematic bias, because it tends to balance all confounding variables, including those which are currently unknown, evenly between intervention and control groups.45 Large observational analyses can minimize random error, but cannot overcome errors arising from systematic bias. Hence the most reliable evidence for future policy will come from large randomized trials, preferably those which incorporate automated targeting of oxygen saturation with predefined settings for alarm limits around each target. v. What do parents and former patients think of the trade-offs between lower mortality and NEC vs lower survival and less ROP, or future trade-offs? Increasingly, using digital technology to seek input from parents and patients will allow their voices to be heard in discussions about trade-offs between competing outcomes in oxygen trials. Such methods could allow parents, former patients, professionals, policymakers and other stakeholders to help prioritize core questions for large international trials. Such trials could evaluate the effects of different oxygen targeting policies on survival as primary outcome, and on disability in survivors as a key secondary outcome.46–48 LACK OF EVIDENCE FROM TRIALS IN MODERATELY PRETERM OR LATE PRETERM INFANTS No trials or systematic reviews have evaluated the effects of different oxygen saturation targets or saturation alarm limits on short- or long-term outcomes in preterm infants of 28 to 36 weeks’ gestation, who may outnumber extremely preterm infants of less than 28 weeks’ gestation by 10-fold or 20-fold.49 This represents a major evidence gap. OBTAINING EVIDENCE FOR FUTURE RECOMMENDATIONS ON OXYGEN TARGETS IN PRETERM INFANTS In 1998, Peto and Baigent wrote,50 “.medical research needs to find practicable ways of greatly increasing the size of randomized studies; otherwise moderate but worthwhile benefits will continue to be missed .” As event rates fall, if mortality and disability are to improve further, large, well-designed perinatal trials with increasingly large sample sizes will be needed.51 Table 4 illustrates the sample sizes needed to detect moderate, worthwhile reductions of 10% and 20% in key outcomes, such as mortality or disability, with adequate power and realistic rates of nonadherence to protocol.52 These sample sizes might mean about 1 additional survivor without major disability for every 50 to 100 patients treated, which many would consider worthwhile for a widely available, affordable treatment like oxygen. All this underlines the need for increasing international collaboration, a major goal of the newly conceived ALPHA Collaboration for Advancing Large, collectively Prioritized perinatal trials of Health outcomes Assessment.46–48 Practice of Oxygen Therapy in Preterm Infants Best Practices What is the current practice for oxygen saturation targeting in infants of less than 28 weeks’ gestation? Surveys conducted in 2015 and 2016 in more than 500 NICUs showed wide variation in practice, with between 60% and 81% of NICUs having increased their median oxygen saturation target ranges by 2% to 5%.34,35 The most up-to-date guidance for practice, published since the NeOProM Collaboration results in 2017 and 2018,1,2 recommends a target range of 91 to 95.30,31 What changes in current practice are likely to improve outcomes? Targeting an oxygen saturation of 91% to 95% will reduce mortality and NEC and increase retinopathy without increasing blindness or disability, compared with targeting an oxygen saturation of 85% to 89%.1,2,7 Targeting an intermediate oxygen-saturation range, such as 87% to 93%, is an untested practice that may increase mortality compared with targeting 91% to 95%, because current oximeters permit increasingly disproportionate exposure to hypoxemia as oxygen saturation decreases to less than 93%.7,41 Is there a Clinical Algorithm? No. New trials are needed in infants of 28 weeks and 0 days to 35 weeks and 6 days gestation to determine which targets minimize mortality and NEC and ROP. However, the incidence of ROP is likely to be proportionately much lower than the incidence of the first 2 outcomes in these infants. Major Recommendations: Adopt a target range of 91% to 95% for oxygen saturation in infants less than 28 weeks’ gestation. Rating for the Strength of the Evidence: High.1 Bibliographic Source(s): Refs.1,2,36,41 ACKNOWLEDGMENT We acknowledge valuable comments by Dr Balpreet Singh, IWK Hospital, Halifax. REFERENCES 1. Askie LM, Darlow BA, Davis PG, et al. Effects of targeting lower versus higher arterial oxygen saturations on death or disability in preterm infants. Cochrane Database Syst Rev 2017;(4):CD011190. 2. Askie LM, Darlow BA, Finer N, et al. Association between oxygen saturation targeting and death or disability in extremely preterm infants in the neonatal oxygenation prospective meta-analysis collaboration. JAMA 2018;319:2190–201. 3. Carlo WA, Finer NN, Walsh MC, et al. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 2010;362:1959–69. 4. Vaucher YE, Peralta-Carcelen M, Finer NN, et al. Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012;367: 2495–504. 5. Schmidt B, Whyte RK, Asztalos EV, et al. 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