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Neurodevelopmental outcomes of preterm infants after randomisation to initial resuscitation with lower (FiO2 <0.3) or higher (FiO2 >0.6) initial oxygen levels. An individual patient meta-analysis
  1. Ju Lee Oei1,2,
  2. Vishal Kapadia3,
  3. Yacov Rabi4,
  4. Ola Didrik Saugstad5,
  5. Denise Rook6,
  6. Marijn J Vermeulen7,
  7. Nuria Boronat8,9,
  8. Valerie Thamrin2,
  9. William Tarnow-Mordi10,
  10. John Smyth1,2,
  11. Ian M Wright11,
  12. Kei Lui1,2,
  13. Johannes B van Goudoever12,13,
  14. Val Gebski10,
  15. Maximo Vento8,9
  1. 1 Newborn Intensive Care Unit, The Royal Hospital for Women, Randwick, New South Wales, Australia
  2. 2 School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia
  3. 3 Department of Pediatrics, Howard Hughes Medical Institute-University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  4. 4 Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada
  5. 5 Department of Pediatric Research, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway
  6. 6 Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands
  7. 7 Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
  8. 8 La Fe Health Research Institute, La Fe University and Polytechnic Hospital, Valencia, Spain
  9. 9 Division of Neonatology, La Fe University and Polytechnic Hospital, Valencia, Spain
  10. 10 NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia
  11. 11 College of Medicine and Dentistry, James Cook University, Cairns, Queensland, Australia
  12. 12 Department of Pediatrics, Emma Children's Hospital AMC, Amsterdam, The Netherlands
  13. 13 Department of Pediatrics, Amsterdam UMC-VUMC location, Amsterdam, The Netherlands
  1. Correspondence to Professor Ju Lee Oei, Newborn Intensive Care Unit, The Royal Hospital for Women, Randwick, New South Wales, Australia; j.oei{at}unsw.edu.au

Abstract

Objective To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO2) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks’ gestation.

Design Meta-analysis of individual patient data from three randomised controlled trials.

Setting Neonatal intensive care units.

Patients 543 children <32 weeks’ gestation.

Intervention Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO2.

Outcome measures Primary: death and/or NDI at 2 years of age.

Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO2) below or at/above 80%.

Results By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO2 was not associated with difference in death and/or disability (difference (95% CI) −0.2%, −7% to 7%, p=0.96) or with cognitive scores <85 (2%, −5% to 9%, p=0.5). Five-minute SpO2 >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO2 ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI.

Conclusion Initial FiO2 was not associated with difference in risk of disability/death at 2 years in infants <32 weeks’ gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed.

  • neonatology
  • resuscitation

Data availability statement

Data are available upon reasonable request. Data used in this study are under the ownership of the investigators of the original randomised controlled trials and were de-identified for analysis in this study.

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Data availability statement

Data are available upon reasonable request. Data used in this study are under the ownership of the investigators of the original randomised controlled trials and were de-identified for analysis in this study.

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Footnotes

  • Contributors JLO developed project idea, performed statistical analysis, drafted the initial manuscript, prepared and approved the final manuscript to be submitted. VK reviewed and approved the final manuscript to be submitted. YR reviewed and approved the final manuscript to be submitted. ODS supervised project and data interpretation, reviewed and approved the final manuscript to be submitted. DR provided data and reviewed and approved the final manuscript to be submitted. MJV provided data and reviewed and approved the final manuscript to be submitted. NB provided data and reviewed and approved the final manuscript to be submitted. VT provided data and reviewed and approved the final manuscript to be submitted. WT-M reviewed and approved the final manuscript to be submitted. JS reviewed and approved the final manuscript to be submitted. IMW reviewed and approved the final manuscript to be submitted. KL reviewed and approved the final manuscript to be submitted. JBvG reviewed and approved the final manuscript to be submitted. VV oversaw statistical analysis and reviewed and approved the final manuscript to be submitted. MV provided data, supervised data interpretation and project, reviewed and approved the final manuscript to be submitted, and provided overall study supervision. The principal investigator (JLO) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding MV acknowledges RETICS funded by the PN 2018-2011 (Spain), ISCIII Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (FEDER), reference RD12/0026. VK acknowledges support by K23HD083511 grant by NIH.

  • Competing interests YR has patents for technology to guide oxygen titration during newborn resuscitation. He did not contribute to any aspects of the manuscript related to the targeting of oxygen saturation.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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