Target Ranges of Oxygen Saturation in Extremely Preterm Infants SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network
01 Jan 2010-
TL;DR: A lower target range of oxygenation, as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe Retinopathy among survivors.
Abstract: Background—Previous studies have suggested that the incidence of retinopathy is lower in preterm infants with exposure to reduced levels of oxygenation than in those exposed to higher levels of oxygenation. However, it is unclear what range of oxygen saturation is appropriate to minimize retinopathy without increasing adverse outcomes. Methods—We performed a randomized trial with a 2-by-2 factorial design to compare target ranges of oxygen saturation of 85 to 89% or 91 to 95% among 1316 infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. The primary outcome was a composite of severe retinopathy of prematurity (defined as the presence of threshold retinopathy, the need for surgical ophthalmologic intervention, or the use of bevacizumab), death before discharge from the hospital, or both. All infants were also randomly assigned to continuous positive airway pressure or intubation and surfactant. Results—The rates of severe retinopathy or death did not differ significantly between the loweroxygen-saturation group and the higher-oxygen-saturation group (28.3% and 32.1%, respectively; relative risk with lower oxygen saturation, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). Death before discharge occurred more frequently in the lower-oxygen-saturation group (in 19.9% of infants vs. 16.2%; relative risk, 1.27; 95% CI, 1.01 to 1.60; P = 0.04), whereas severe retinopathy among survivors occurred less often in this group (8.6% vs. 17.9%; relative risk, 0.52; 95% CI, 0.37 to 0.73; P<0.001). There were no significant differences in the rates of other adverse events. Conclusions—A lower target range of oxygenation (85 to 89%), as compared with a higher range (91 to 95%), did not significantly decrease the composite outcome of severe retinopathy or death, but it resulted in an increase in mortality and a substantial decrease in severe retinopathy among survivors. The increase in mortality is a major concern, since a lower target range of oxygen saturation is increasingly being advocated to prevent retinopathy of prematurity. (ClinicalTrials.gov number, NCT00233324.) Retinopathy of prematurity is an important cause of blindness and other visual disabilities in preterm infants. The incidence of retinopathy of prematurity was increased with exposure to unrestricted oxygen supplementation in preterm infants in randomized, controlled trials
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Emory University1, United States Environmental Protection Agency2, University of Iowa3, Case Western Reserve University4, University of Alabama at Birmingham5, Wayne State University6, Brown University7, Ohio State University8, Lucile Packard Children's Hospital9, Stanford University10, University of Texas Southwestern Medical Center11, RTI International12, Cincinnati Children's Hospital Medical Center13, Indiana University14, University of Texas Health Science Center at Houston15, Duke University16, University of New Mexico17, University of Rochester18, University of Pennsylvania19, Children's Mercy Hospital20, University of California, Los Angeles21, National Institutes of Health22
TL;DR: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased.
Abstract: Importance Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality. Objective To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers. Design, Setting, Participants Prospective registry of 34 636 infants, 22 to 28 weeks’ gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012. Exposures Extremely preterm birth. Main Outcomes and Measures Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex. Results Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants];P Conclusions and Relevance Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks’ gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions. Trial Registration clinicaltrials.gov Identifier:NCT00063063.
1,818 citations
TL;DR: Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids to promote normal growth and limit suppression of neurovascular development.
1,001 citations
Emory University1, RTI International2, University of Iowa3, Case Western Reserve University4, University of Alabama at Birmingham5, Wayne State University6, Brown University7, Ohio State University8, Lucile Packard Children's Hospital9, Stanford University10, University of Texas Southwestern Medical Center11, Cincinnati Children's Hospital Medical Center12, Indiana University13, University of Texas Health Science Center at Houston14, Duke University15, University of New Mexico16, University of Rochester17, University of Pennsylvania18, Children's Mercy Hospital19, University of California, Los Angeles20, National Institutes of Health21
TL;DR: There have been considerable changes in care for mothers in preterm labor and for extremely preterm infants since the 1990s, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network has monitored changes.
Abstract: Obstet Gynecol Surv 2016;71(1):7–9Since the 1990s, there have been considerable changes in care for mothers in preterm labor and for extremely preterm infants. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network has monitored changes in this
591 citations
TL;DR: The third update of the European Guidelines for the Management of RDS by a European panel of expert neonatologists including input from an expert perinatal obstetrician based on available literature up to the beginning of 2016 is reported.
Abstract: Advances in the management of respiratory distress syndrome (RDS) ensure that clinicians must continue to revise current practice. We report the third update of the European Guidelines for the Management of RDS by a European panel of expert neonatologists including input from an expert perinatal obstetrician based on available literature up to the beginning of 2016. Optimizing the outcome for babies with RDS includes consideration of when to use antenatal steroids, and good obstetric practice includes methods of predicting the risk of preterm delivery and also consideration of whether transfer to a perinatal centre is necessary and safe. Methods for optimal delivery room management have become more evidence based, and protocols for lung protection, including initiation of continuous positive airway pressure and titration of oxygen, should be implemented from soon after birth. Surfactant replacement therapy is a crucial part of the management of RDS, and newer protocols for surfactant administration are aimed at avoiding exposure to mechanical ventilation, and there is more evidence of differences among various surfactants in clinical use. Newer methods of maintaining babies on non-invasive respiratory support have been developed and offer potential for greater comfort and less chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease although minimizing the time spent on mechanical ventilation using caffeine and if necessary postnatal steroids are also important considerations. Protocols for optimizing the general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome.
521 citations
TL;DR: Recent experiences in neonatology suggest that combining less invasive care strategies that avoid excessive oxygen and ventilation, decrease postnatal infections, and optimize nutrition may decrease the incidence and severity of BPD.
Abstract: Purpose of review Bronchopulmonary dysplasia (BPD) remains the most common severe complication of preterm birth. A number of recent animal models and clinical studies provide new information about pathophysiology and treatment. Recent findings The epidemiology of BPD continues to demonstrate that birth weight and gestational age are most predictive of BPD. Correlations of BPD with chorioamnionitis are clouded by the complexity of the fetal exposures to inflammation. Excessive oxygen use in preterm infants can increase the risk of BPD but low saturation targets may increase death. Numerous recent trials demonstrate that many preterm infants can be initially stabilized after delivery with continuous positive airway response (CPAP) and then be selectively treated with surfactant for respiratory distress syndrome. The growth of the lungs of the infant with BPD through childhood remains poorly characterized. Summary Recent experiences in neonatology suggest that combining less invasive care strategies that avoid excessive oxygen and ventilation, decrease postnatal infections, and optimize nutrition may decrease the incidence and severity of BPD.
476 citations
References
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TL;DR: Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes to a clinically important degree and led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP.
Abstract: Objective: To determine whether earlier treatment using ablation of the avascular retina in high-risk prethreshold retinopathy of prematurity (ROP) results in improved grating visual acuity and retinal structural outcomes compared with conventional treatment. Methods: Infants with bilateral high-risk prethreshold ROP (n=317) had one eye randomized to early treatment with the fellow eye managed conventionally (control eye). In asymmetric cases (n=84), the eye with high-risk prethreshold ROP was randomized to early treatment or conventional management. High risk was determined using a model based on the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity natural history cohort. At a corrected age of 9 months, visual acuity was assessed by masked testers using the Teller acuity card procedure. At corrected ages of 6 and 9 months, eyes were examined for structural outcome. Outcomes for the 2 treatment groups of eyes were compared using X 2 analysis, combining data for bilateral and asymmetric cases. Results: Grating acuity results showed a reduction in unfavorable visual acuity outcomes with earlier treatment, from 19.5% to 14.5% (P=.01). Unfavorable structural outcomes were reduced from 15.6% to 9.1% (P<.001) at 9 months. Further analysis supported retinal ablative therapy for eyes with type 1 ROP, defined as zone I, any stage ROP with plus disease (a degree of dilation and tortuosity of the posterior retinal blood vessels meeting or exceeding that of a standard photograph); zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 ROP with plus disease. The analysis supported a wait-and-watch approach to type 2 ROP, defined as zone 1, stage 1 or 2 ROP without plus disease or zone II, stage 3 ROP without plus disease. These eyes should be considered for treatment only if they progress to type 1 or threshold ROP. Conclusions: Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes to a clinically important degree. Additional analyses led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP. Long-term follow-up is being conducted to learn whether the benefits noted in the first year after birth will persist into childhood.
1,032 citations
TL;DR: Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes to a clinically important degree and led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP.
Abstract: OBJECTIVE
To determine whether earlier treatment using ablation of the avascular retina in high-risk prethreshold retinopathy of prematurity (ROP) results in improved grating visual acuity and retinal structural outcomes compared with conventional treatment.
METHODS
Infants with bilateral high-risk prethreshold ROP (n = 317) had one eye randomized to early treatment with the fellow eye managed conventionally (control eye). In asymmetric cases (n = 84), the eye with high-risk prethreshold ROP was randomized to early treatment or conventional management. High risk was determined using a model based on the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity natural history cohort. At a corrected age of 9 months, visual acuity was assessed by masked testers using the Teller acuity card procedure. At corrected ages of 6 and 9 months, eyes were examined for structural outcome. Outcomes for the 2 treatment groups of eyes were compared using chi2 analysis, combining data for bilateral and asymmetric cases.
RESULTS
Grating acuity results showed a reduction in unfavorable visual acuity outcomes with earlier treatment, from 19.5% to 14.5% (P =.01). Unfavorable structural outcomes were reduced from 15.6% to 9.1% (P<.001) at 9 months. Further analysis supported retinal ablative therapy for eyes with type 1 ROP, defined as zone I, any stage ROP with plus disease (a degree of dilation and tortuosity of the posterior retinal blood vessels meeting or exceeding that of a standard photograph); zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 ROP with plus disease. The analysis supported a wait-and-watch approach to type 2 ROP, defined as zone I, stage 1 or 2 ROP without plus disease or zone II, stage 3 ROP without plus disease. These eyes should be considered for treatment only if they progress to type 1 or threshold ROP.
CONCLUSIONS
Early treatment of high-risk prethreshold ROP significantly reduced unfavorable outcomes to a clinically important degree. Additional analyses led to modified recommendations for the use of peripheral retinal ablation in eyes with ROP. Long-term follow-up is being conducted to learn whether the benefits noted in the first year after birth will persist into childhood.
1,027 citations
University of California, San Diego1, University of Alabama at Birmingham2, Case Western Reserve University3, Brown University4, University of Utah5, University of Cincinnati6, Tufts University7, Emory University8, University of Texas Southwestern Medical Center9, University of Texas Health Science Center at Houston10, University of Rochester11, Indiana University12, Duke University13, Stanford University14, University of Miami15, Wayne State University16, Wake Forest University17, University of Iowa18, Yale University19, University of New Mexico20, National Institutes of Health21
TL;DR: The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants.
Abstract: BACKGROUND There are limited data to inform the choice between early treatment with continuous positive airway pressure (CPAP) and early surfactant treatment as the initial support for extremely-low-birth-weight infants. METHODS We performed a randomized, multicenter trial, with a 2-by-2 factorial design, involving infants who were born between 24 weeks 0 days and 27 weeks 6 days of gestation. Infants were randomly assigned to intubation and surfactant treatment (within 1 hour after birth) or to CPAP treatment initiated in the delivery room, with subsequent use of a protocol-driven limited ventilation strategy. Infants were also randomly assigned to one of two target ranges of oxygen saturation. The primary outcome was death or bronchopulmonary dysplasia as defined by the requirement for supplemental oxygen at 36 weeks (with an attempt at withdrawal of supplemental oxygen in neonates who were receiving less than 30% oxygen). RESULTS A total of 1316 infants were enrolled in the study. The rates of the primary outcome did not differ significantly between the CPAP group and the surfactant group (47.8% and 51.0%, respectively; relative risk with CPAP, 0.95; 95% confidence interval [CI], 0.85 to 1.05) after adjustment for gestational age, center, and familial clustering. The results were similar when bronchopulmonary dysplasia was defined according to the need for any supplemental oxygen at 36 weeks (rates of primary outcome, 48.7% and 54.1%, respectively; relative risk with CPAP, 0.91; 95% CI, 0.83 to 1.01). Infants who received CPAP treatment, as compared with infants who received surfactant treatment, less frequently required intubation or postnatal corticosteroids for bronchopulmonary dysplasia (P<0.001), required fewer days of mechanical ventilation (P=0.03), and were more likely to be alive and free from the need for mechanical ventilation by day 7 (P=0.01). The rates of other adverse neonatal outcomes did not differ significantly between the two groups. CONCLUSIONS The results of this study support consideration of CPAP as an alternative to intubation and surfactant in preterm infants. (ClinicalTrials.gov number, NCT00233324.)
959 citations
TL;DR: It is suggested that infants without plus disease may be more responsive to supplemental therapy than infants with plus disease, and ROP progression rates were lower with supplemental oxygen than with conventional oxy- gen, but the differences were not statistically significant.
Abstract: Objective. To determine the efficacy and safety of supplemental therapeutic oxygen for infants with prethreshold retinopathy of prematurity (ROP) to reduce the probability of progression to threshold ROP and the need for peripheral retinal ablation. Methods. Premature infants with confirmed pre- threshold ROP in at least 1 eye and median pulse oxim- etry <94% saturation were randomized to a conventional oxygen arm with pulse oximetry targeted at 89% to 94% saturation or a supplemental arm with pulse oximetry targeted at 96% to 99% saturation, for at least 2 weeks, and until both eyes were at study endpoints. Certified examiners masked to treatment assignment conducted weekly eye examinations until each study eye reached ophthalmic endpoint. An adverse ophthalmic endpoint for an infant was defined as reaching threshold criteria for laser or cryotherapy in at least 1 study eye. A favor- able ophthalmic endpoint was regression of the ROP into zone III for at least 2 consecutive weekly examinations or full retinal vascularization. At 3 months after the due date of the infant, ophthalmic findings, pulmonary sta- tus, growth, and interim illnesses were again recorded. Results. Six hundred forty-nine infants (325 conven- tional and 324 supplemental) were enrolled from 30 cen- ters over 5 years. Five hundred ninety-seven (92.0%) in- fants attained known ophthalmic endpoints, and 600 (92%) completed the ophthalmic 3-month assessment. The rate of progression to threshold in at least 1 eye was 48% in the conventional arm and 41% in the supplemen- tal arm. After adjustment for baseline ROP severity stra- tum, plus disease, race, and gestational age, the odds ratio (supplemental vs conventional) for progression was .72 (95% confidence interval: .52, 1.01). Final structural status of all study eyes at 3 months of corrected age showed similar rates of severe sequelae in both treatment arms: retinal detachments or folds (4.4% conventional vs 4.1% supplemental), and macular ectopia (3.9% conven- tional vs 3.9% supplemental). Within the prespecified ROP severity strata, ROP progression rates were lower with supplemental oxygen than with conventional oxy- gen, but the differences were not statistically significant. A post hoc subgroup analysis of plus disease (dilated and tortuous vessels in at least 2 quadrants of the posterior pole) suggested that infants without plus disease may be more responsive to supplemental therapy (46% progres- sion in the conventional arm vs 32% in the supplemental arm) than infants with plus disease (52% progression in
590 citations
Case Western Reserve University1, RTI International2, Yale University3, Emory University4, University of Alabama5, Brown University6, University of Miami7, Wake Forest University8, University of Texas Southwestern Medical Center9, Wayne State University10, Duke University11, University of Rochester12, University of Cincinnati13, Indiana University14, Stanford University15, University of Texas at Austin16
TL;DR: The physiologic definition of BPD facilitates the measurement of B PD as an outcome in clinical trials and the comparison between and within centers over time, and reduced the variation among centers.
Abstract: Objective. Bronchopulmonary dysplasia (BPD) is the endpoint of many intervention trials in neonatology, yet the outcome measure when based solely on oxygen administration may be confounded by differing criteria for oxygen administration between physicians. We previously reported a technique to standardize the definition of BPD between sites by using a timed room-air challenge in selected infants. We hypothesized that a physiologic definition of BPD would reduce the variation in observed rates of BPD among different neonatal centers. Methodology. A total of 1598 consecutive inborn premature infants (501–1249 g birth weight) who remained hospitalized at 36 weeks9 postmenstrual age were prospectively assessed and assigned an outcome with both a clinical definition and physiologic definition of BPD. The clinical definition of BPD was oxygen supplementation at exactly 36 weeks9 postmenstrual age. The physiologic definition of BPD was assigned at 36 ± 1 weeks9 postmenstrual age and included 2 distinct subpopulations. First, neonates on positive pressure support or receiving >30% supplemental oxygen with saturations between 90% and 96% were assigned the outcome BPD and not tested further. Second, those receiving ≤30% oxygen or effective oxygen >30% with saturations >96% underwent a room-air challenge with continuous observation and oxygen-saturation monitoring. Outcomes of the room-air challenge were “no BPD” (saturations ≥90% during weaning and in room air for 30 minutes) or “BPD” (saturation Results. A total of 560 (35.0%) neonates were diagnosed with BPD by the clinical definition of oxygen use at 36 weeks9 postmenstrual age. The physiologic definition diagnosed BPD in 398 (25.0%) neonates in the cohort. All infants were safely studied. There were marked differences in the impact of the definition on BPD rates between centers (mean reduction: 10%; range: 0–44%). Sixteen centers had a decrease in their BPD rate, and 1 center had no change in their rate. Conclusions. The physiologic definition of BPD reduced the overall rate of BPD and reduced the variation among centers. Significant center differences in the impact of the physiologic definition were seen, and differences remained even with the use of this standardized definition. The magnitude of the change in BPD rate is comparable to the magnitude of treatment effects seen in some clinical trials in BPD. The physiologic definition of BPD facilitates the measurement of BPD as an outcome in clinical trials and the comparison between and within centers over time.
553 citations