This study is designed to answer one of the fundamental gaps in knowledge in the
      resuscitation of preterm infants at birth: What is the optimal target oxygen saturation
      (SpO2) range that increases survival without long-term morbidities? Oxygen (O2) is routinely
      used for the stabilization of preterm infants in the delivery room (DR), but its use is
      linked with mortality and several morbidities including bronchopulmonary dysplasia (BPD). To
      balance the need to give sufficient O2 to correct hypoxia and avoid excess O2, the neonatal
      resuscitation program (NRP) recommends initiating preterm resuscitation with low (≤ 30%)
      inspired O2 concentration (FiO2) and subsequent titration to achieve a specified target SpO2
      range. These SpO2 targets are based on approximated 50th percentile SpO2 (Sat50) observed in
      healthy term infants. However, the optimal SpO2 targets remain undefined in the preterm
      infants. Recent data suggest that the current SpO2 targets (Sat50) may be too low. The
      investigators plan to conduct a multicenter RCT of Sat75 versus Sat50 powered for survival
      without BPD. The investigators will randomize 700 infants, 23 0/7- 30 6/7 weeks' GA, to 75th
      percentile SpO2 goals (Sat75, Intervention) or 50th percentile SpO2 goals (Sat50, control).
      Except for the SpO2 targets, all resuscitations will follow NRP guidelines including an
      initial FiO2 of 0.3. In Aim 1, the investigators will determine whether targeting Sat75
      compared to Sat50 increases survival without lung disease (BPD). In addition, the
      investigators will compare the rates of other major morbidities such as IVH. In Aim 2, the
      investigators will determine whether targeting Sat75 compared to Sat50 increases survival
      without neurodevelopmental impairment at 2 years of age. In Aim 3, the investigators will
      determine whether targeting Sat75 compared to Sat50 decreases oxidative stress.

Optimization of Saturation Targets And Resuscitation Trial (OptiSTART)

Premature Infants

Bronchopulmonary Dysplasia

Intraventricular Hemorrhage

Neurodevelopmental Outcomes

Purpose: Oxygen is the most commonly used drug during preterm resuscitation, but its use has
      been linked to mortality and several morbidities such as bronchopulmonary dysplasia (BPD),
      intraventricular hemorrhage (IVH), and retinopathy of prematurity (ROP).Preterm infants at
      birth are more vulnerable to oxygen toxicity caused by exposure to high concentrations of
      oxygen during resuscitation, but are also equally vulnerable to the adverse effects of
      suboptimal oxygen use in the delivery room. To balance the need to give sufficient O2 to
      correct hypoxia and to avoid excess O2, the NRP recommends initiating preterm resuscitation
      with low FiO2 (≤ 0.3) and subsequent titration to achieve specified target O2 saturations
      (SpO2). These SpO2 targets (Sat50) are based on approximated 50th percentile SpO2 values of
      minute per minute pre-ductal SpO2 observed in healthy term newborns who were born vaginally
      at sea level, breathing spontaneously and did not need any oxygen at birth. Current SpO2
      targets are based on expert opinion. In the absence of studies comparing different SpO2
      targets, Sat50 was selected by experts at the International Liaison Committee On
      Resuscitation (ILCOR) and NRP to balance the need for O2 supplementation and avoid excess O2
      exposure. Ranges were adjusted by NRP so that they could be memorized easily. However, a
      recently published study suggested that the currently recommended Sat50 targets are lower
      than 50th percentile SpO2 values for term infants who undergo delayed cord clamping. Recent
      studies suggest that the currently recommended Sat50 SpO2 targets may be too low to promote
      an adequate drop in pulmonary vascular resistance in preterm infants and may be harmful.
      Recent studies raise concern that the Sat50 strategy may be associated with poorer breathing
      efforts, higher IVH and higher mortality. The majority of research in O2 use during preterm
      resuscitation has focused on the starting FiO2, while SpO2 targets have received very little
      attention. The investigators propose a paradigm shift by changing the research focus to
      determine the optimal target SpO2 range instead of the initial FiO2. The investigators
      propose a novel O2 strategy where resuscitation is initiated with 0.3 FiO2 and is titrated
      every 30 seconds to meet target SpO2 roughly based on the 75th percentile of Dawson curves
      (Sat75) compared to the 50th percentile of Dawson curves (Sat50). Preliminary data from
      principal investigator's NICHD K23 funded pilot RCT of 75 preterm infants <31 weeks'
      gestational age (GA) demonstrated that infants randomized to 75th percentile SpO2 goals
      (Sat75) had a lower incidence of SpO2 <80% at five minutes and lower duration of bradycardia
      and PPV in the DR compared to infants randomized to 50th percentile SpO2 goals (Sat50).
      Although not powered for this analysis, Sat75 infants had less pulmonary hypertension and
      higher survival without BPD. The investigators hypothesize that the Sat75 strategy results in
      better pulmonary transition, less time with low SpO2 and lower oxidative stress resulting in
      a lower incidence of neonatal morbidities such as BPD, IVH, ROP and higher survival without
      BPD.

      Hypothesis: The primary hypothesis is that delivery room resuscitation of preterm infants <
      31 weeks' GA with Sat75 targets compared to Sat50 targets will result in increased survival
      without BPD at 36 weeks' postmenstrual age (PMA).

      Study design: A prospective multicenter randomized controlled trial of Sat75 versus Sat50
      will be conducted. As per the current NRP guidelines, resuscitation will be initiated with
      0.3 FiO2 in both intervention and control groups. The study intervention is the Sat75 where
      FiO2 will be titrated every 30 seconds by 0.1-0.2 to achieve target SpO2 that approximates
      the 75th percentile SpO2 observed in healthy term newborns. The control group is the Sat50
      where FiO2 will be titrated by 0.2-0.3 every 30 seconds to achieve the NRP recommended target
      SpO2 which approximates the 50th percentile SpO2 observed in healthy term newborns. In the
      rare event, where chest compressions are needed during delivery room resuscitation, the FiO2
      will be increased to 1.0 as per current NRP guidelines. Once the heart rate (HR) is
      stabilized, the FiO2 will be reduced to meet the target SpO2. Apart from the randomly
      assigned target SpO2, resuscitation will follow current NRP guidelines. Assignment to the
      Sat75 or Sat50 group will use a 1:1 allocation ratio and stratification by GA: 23 0/7 to 27
      6/7 weeks and 28 0/7 to 30 6/7 weeks. Demographics, perinatal variables, resuscitation
      characteristics and neonatal morbidity-mortality data and data of Neurodevelopmental
      follow-up at around 2 years of age will be electronically recorded using the web-based data
      entry system developed by the Data Coordinating Center.

      Analysis plan: An intention to treat analysis of all randomized infants who received study
      intervention and have a post-randomization study measurement will be conducted. Baseline
      characteristics of the newborns will be compared between treatment groups. Descriptive
      statistics such as mean, SD, median, and range will be used to summarize continuous variables
      in each study group; frequencies and percentages will be presented for categorical variables.
      The groups will be formally compared using Student's t-tests and Wilcoxon rank-sum tests, as
      appropriate, for continuous variables. The chi-square test of association and Fisher's exact
      test will be used for categorical variables as appropriate.

      The primary analysis will be based on the chi-square test of association. Rates of survival
      without BPD will be presented with 95% confidence intervals. Multivariable logistic
      regression models (for odds ratios), or modified Poisson regression models with robust
      standard errors (for risk ratios), will be used to adjust for any imbalanced baseline
      characteristics. Any characteristics identified as being imbalanced at baseline will be
      considered as covariates. The primary analysis plan assumes that the intra-class correlation
      among infants of multiple gestations will be negligible. As sensitivity analyses, generalized
      estimating equations with robust standard errors will be used to account for clustering
      effects within siblings. Statistical analysis will be performed with SAS software version 9.4
      (SAS Institute, Cary NC). A two-sided 0.05 level of significance will be used and no interim
      analysis is planned. Data collection protocols will be implemented to minimize missing data.
      The investigators will conduct 'Per Protocol' analysis and 'As Treated' analysis strictly as
      secondary analyses to evaluate the impact of time spent outside the group target SpO2 on
      clinical outcomes. Further, the investigators will conduct pre-planned analyses to examine
      possible site by testing site by treatment interactions.

Sat75

Sat50

Optimization of Saturation Targets And Resuscitation (OptiSTART): Multicenter Randomized Controlled Trial

The primary outcome for this trial is survival without BPD at 36 weeks' PMA. Both components, death and BPD, will also be reported separately. Neonatal mortality during the NICU stay, the postnatal day at the time of mortality and the primary cause of mortality will be recorded. BPD will be defined as the need for any form of positive airway pressure support or supplemental O2 at 36 weeks' PMA.BPD will be graded as mild, moderate and severe as per the NICHD consensus definition. All eligible infants will undergo room air challenge at 36 weeks' PMA for the physiologic definition of BPD.

Associate Professor

BPD will be defined as the need for any form of positive airway pressure support or supplemental O2 at 36 weeks' PMA.BPD will be graded as mild, moderate and severe as per the NICHD consensus definition. All eligible infants will undergo room air challenge at 36 weeks' PMA for the physiologic definition of BPD. In addition, BPD by Jensen Criteria will also be used as a secondary outcome. Respiratory support at 40 weeks PMA and at discharge will also be collected

High resolution SpO2 data with 2 second frequency from pulse oximeter will be collected. Average Spo2 value every 30 seconds will be plotted. The investigators will also calculate time spent in the desired target, above the target or below the target.

The investigators will record if the newborn was intubated in the delivery room

In the rare event of the need for full CPR, data will be abstracted from the DR code documentation. FiO2 will be adjusted to 1.0 until return of spontaneous circulation and then titrated to achieve the randomized target SpO2.

Necrotizing enterocolitis will be defined ≥ Stage 2 based on the modified Bell criteria.

Moderate to severe neurodevelopmental impairment will be defined as Bayley III Cognitive <85, Bayley III Motor <85, gross motor functional classification system (GMFCS) 2 or greater, or bilateral "blind" despite corrective lenses or bilateral no functional hearing with or without amplification

8-Isoprostanes and 8-OHdG will be measured in serum and urine samples

FiO2 will be titrated every 30 seconds by 0.2-0.3 to achieve target SpO2 that approximates the 75th percentile SpO2 observed in healthy term newborns. Percentiles are roughly based on Dawson reference curves of healthy term infants after birth.

FiO2 will be titrated every 30 seconds by 0.1-0.2 to achieve NRP recommended target SpO2 which approximates the 50th percentile SpO2 observed in healthy term newborns. Percentiles are roughly based on Dawson reference curves of healthy term infants after birth.

Optimization of Saturation Targets And Resuscitation Trial (OptiSTART)

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