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Original article
Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study
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  1. Ulrich H Thome1,
  2. Orsolya Genzel-Boroviczeny2,
  3. Bettina Bohnhorst3,
  4. Manuel Schmid4,
  5. Hans Fuchs5,
  6. Oliver Rohde6,
  7. Stefan Avenarius7,
  8. Hans-Georg Topf8,
  9. Andrea Zimmermann9,
  10. Dirk Faas10,
  11. Katharina Timme11,
  12. Barbara Kleinlein12,
  13. Horst Buxmann13,
  14. Wilfried Schenk14,
  15. Hugo Segerer15,
  16. Norbert Teig16,
  17. Annett Bläser1,
  18. Roland Hentschel5,
  19. Matthias Heckmann17,
  20. Rolf Schlösser13,
  21. Jochen Peters12,
  22. Rainer Rossi11,
  23. Wolfgang Rascher8,
  24. Ralf Böttger7,
  25. Jürgen Seidenberg6,
  26. Gesine Hansen3,
  27. Maria Zernickel4,
  28. Harald Bode18,
  29. Jens Dreyhaupt19,
  30. Rainer Muche19,
  31. Helmut D Hummler4
  32. for the PHELBI Study Group
  1. 1 Division of Neonatology, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
  2. 2 Division of Neonatology, IS Dr. von Hauner University Children's Hospital, Ludwig Maximilian University of Munich, München, Germany
  3. 3 Division of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
  4. 4 Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, University of Ulm, Ulm, Baden-Württemberg, Germany
  5. 5 Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, Albert Ludwigs University Freiburg, Freiburg, Germany
  6. 6 Division of Neonatology and Pediatric Critical Care, Elisabeth Children's Hospital, Klinikum Oldenburg, Medical Campus, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany
  7. 7 Hospital for General Pediatrics and Neonatology, Otto von Guericke University Magdeburg, Magdeburg, Germany
  8. 8 Division of Neonatology, University Hospital for Children and Adolescents, Friedrich-Alexander University Erlangen, Erlangen, Germany
  9. 9 Mutter-Kind-Zentrum, Klinikum rechts der Isar, Technical University of Munich, München, Germany
  10. 10 University Hospital for General Pediatrics and Neonatology, Justus Liebig University Giessen, Giessen, Germany
  11. 11 Division of Neonatology, Hospital for Children and Adolescents, Vivantes-Hospital Neukölln, Berlin, Germany
  12. 12 Hospital for Children and Adolescents, Children's Hospital of the Third Order, Munich, Germany
  13. 13 Division of Neonatology, University Hospital for Children and Adolescents of the J.W. Goethe University Frankfurt/Main, Frankfurt am Main, Germany
  14. 14 Hospital for Children and Adolescents, Central Hospital Augsburg, Augsburg, Germany
  15. 15 St. Hedwig Hospital, University of Regensburg (H.S.), Regensburg, Germany
  16. 16 Department of Neonatology and Pediatric Intensive Care, Katholisches Klinikum, Ruhr University Bochum, Bochum, Germany
  17. 17 Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, Ernst Moritz Arndt University Greifswald, Greifswald, Germany
  18. 18 Division of Neuropediatrics, University Hospital for Children and Adolescents, University of Ulm, Ulm, Germany
  19. 19 Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
  1. Correspondence to Professor Ulrich Thome, Division of Neonatology, Department of Women's and Children's Medicine, University Hospital of Leipzig, Liebigstrasse 20a, Leipzig 04103, Germany

Abstract

Background Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial.

Methods Infants (n=359) between 400 and 1000 g birth weight and 23 0/7–28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI).

Results There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60–96, high target) and 84 (58–96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57–100) and 84 (65–96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment.

Conclusions A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option.

Trial registration number ISRCTN56143743.

  • neurodevelopmental outcome
  • permissive hypercapnia
  • Bayley scales
  • bronchopulmonary dysplasia
  • intraventricular haemorrhage

https://doi.org/10.1136/archdischild-2016-311581

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    Footnotes

    • Collaborators Further study group members are listed in online supplementary appendix 1, recruiting perinatal centres in online supplementary appendix 2.

    • Contributors UHT: study coordinator, lead investigator, wrote the grant application, wrote the institutional review board application, developed and drafted the study protocol, codeveloped the statistical analysis plan, recruited patients, gathered data, wrote the manuscript. OG-B: developed the study protocol, recruited patients, gathered data, edited the manuscript. BB: developed the study protocol, recruited patients, gathered data, edited the manuscript. MS: developed the study protocol, recruited patients, gathered data, edited the manuscript. HF: developed the study protocol, recruited patients, gathered data, edited the manuscript. OR: developed the study protocol, recruited patients, gathered data, edited the manuscript. SA: developed the study protocol, recruited patients, gathered data, edited the manuscript. H-GT: recruited patients, gathered data, edited the manuscript. AZ: developed the study protocol, recruited patients, gathered data, edited the manuscript. DF: developed the study protocol, recruited patients, gathered data, edited the manuscript. KT: recruited patients, gathered data, edited the manuscript. BK: developed the study protocol, recruited patients, gathered data, edited the manuscript. HB: developed the study protocol, recruited patients, gathered data, edited the manuscript. WS: developed the study protocol, recruited patients, gathered data, edited the manuscript. HS: developed the study protocol, recruited patients, gathered data, edited the manuscript. NT: developed the study protocol, recruited patients, gathered data, edited the manuscript. AB: recruited patients, gathered data, edited the manuscript. RH: developed the study protocol, recruited patients, gathered data, edited the manuscript. MH: developed the study protocol, recruited patients, edited the manuscript. RS: developed the study protocol, recruited patients, edited the manuscript. JP: developed the study protocol, recruited patients, edited the manuscript. RR: developed the study protocol, recruited patients, edited the manuscript. WR: developed the study protocol, edited the manuscript. RB: recruited patients, gathered data, edited the manuscript. JS: developed the study protocol, recruited patients, edited the manuscript. GH: developed the study protocol, edited the manuscript. MZ: programmed the study database, responsible for data management, query management and data entry, edited the manuscript. HB: developed the Elternfragebogen zur kindlichen Entwicklung im Kleinkindalter (German version of CDI) and gave advice about its use in the trial, edited the manuscript. JD: developed the final statistical analysis plan and the protocol amendment, provided statistical analysis, edited the manuscript. RM: developed the study protocol, developed the initial statistical analysis plan, calculated sample size, edited the manuscript. HDH: conceived the idea for this study, edited the grant application, developed the study protocol, recruited patients, gathered data, edited the manuscript.

    • Funding The trial was funded by taxpayer funds through the Deutsche Forschungsgemeinschaft (German Research Foundation, project number Th626/5-1). Aside from extensive review by anonymous expert reviewers, the funding agency had no other role in study design, data collection, analysis or interpretation, nor indeed in writing this report. Access to the raw data was limited to the data manager (MZ) and the statistician (JD). The corresponding author (UHT) had full access to all of the data and ultimate responsibility for submission for publication.

    • Competing interests None declared.

    • Patient consent Parental/guardian consent obtained.

    • Ethics approval All institutional review boards of all participating hospitals.

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