title: Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial.
abstract: BACKGROUND
  Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death.
  
  
  METHODS
  In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743.
  
  
  RESULTS
  Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36).
  
  
  CONCLUSIONS
  Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection.
  
  
  BACKGROUND
  Deutsche Forschungsgemeinschaft.
authors.affiliation: Division of Neonatology, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany. Electronic address: uhthome@web.de.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Thome
authors.affiliation: Division of Neonatology, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Genzel-Boroviczeny
authors.affiliation: Division of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bohnhorst
authors.affiliation: Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, University of Ulm, Ulm, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: Division of Neonatology and Pediatric Critical Care, Elisabeth Children's Hospital, Klinikum Oldenburg, Medical Campus, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rohde
authors.affiliation: Hospital for General Pediatrics and Neonatology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Avenarius
authors.affiliation: Division of Neonatology, University Hospital for Children and Adolescents, Friedrich-Alexander University Erlangen, Erlangen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Topf
authors.affiliation: Mutter-Kind-Zentrum, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: University Hospital for General Pediatrics and Neonatology, Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Faas
authors.affiliation: Division of Neonatology, Hospital for Children and Adolescents, Vivantes-Hospital Neukölln, Berlin, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Timme
authors.affiliation: Hospital for Children and Adolescents, Children's Hospital of the Third Order, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kleinlein
authors.affiliation: Division of Neonatology, University Hospital for Children and Adolescents of the J.W. Goethe University Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Buxmann
authors.affiliation: Hospital for Children and Adolescents, Central Hospital Augsburg, Augsburg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Schenk
authors.affiliation: St. Hedwig Hospital, University of Regensburg, Regensburg, Germany.
authors.forename: Hugo
authors.initials: H
authors.lastname: Segerer
authors.affiliation: Department of Neonatology and Pediatric Intensive Care, Katholisches Klinikum, Ruhr University Bochum, Bochum, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Teig
authors.affiliation: Division of Neonatology, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Gebauer
authors.affiliation: Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, Albert Ludwigs University Freiburg, Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Hentschel
authors.affiliation: Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heckmann
authors.affiliation: Division of Neonatology, University Hospital for Children and Adolescents of the J.W. Goethe University Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schlösser
authors.affiliation: Hospital for Children and Adolescents, Children's Hospital of the Third Order, Munich, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Peters
authors.affiliation: Division of Neonatology, Hospital for Children and Adolescents, Vivantes-Hospital Neukölln, Berlin, Berlin, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Rossi
authors.affiliation: Division of Neonatology, University Hospital for Children and Adolescents, Friedrich-Alexander University Erlangen, Erlangen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rascher
authors.affiliation: Hospital for General Pediatrics and Neonatology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Böttger
authors.affiliation: Division of Neonatology and Pediatric Critical Care, Elisabeth Children's Hospital, Klinikum Oldenburg, Medical Campus, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seidenberg
authors.affiliation: Division of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Hansen
authors.affiliation: Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, University of Ulm, Ulm, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Zernickel
authors.affiliation: Division of Pediatric Radiology, University Hospital of the Justus Liebig University Giessen, Giessen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Alzen
authors.affiliation: Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Dreyhaupt
authors.affiliation: Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Muche
authors.affiliation: Division of Neonatology and Pediatric Critical Care, University Hospital for Children and Adolescents, University of Ulm, Ulm, Germany.
authors.forename: Helmut D
authors.initials: HD
authors.lastname: Hummler
mesh_terms: D001997:Bronchopulmonary Dysplasia / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D002245:Carbon Dioxide / Q000097:blood*; D005260:Female; D005865:Gestational Age; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000097:blood / Q000503:physiopathology; D052577:Infant, Extremely Low Birth Weight / Q000097:blood* / Q000502:physiology; D062071:Infant, Extremely Premature / Q000097:blood* / Q000502:physiology; D007231:Infant, Newborn; D008297:Male; D010313:Partial Pressure; D012121:Respiration, Artificial / Q000379:methods; D013990:Tidal Volume / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D002245:Carbon Dioxide