Early biomarkers of brain injury and cerebral hypo- and hyperoxia in the SafeBoosC II trial.
BACKGROUND
The randomized clinical trial, SafeBoosC II, examined the effect of monitoring of cerebral oxygenation by near-infrared spectroscopy combined with a guideline on treatment when cerebral oxygenation was out of the target range. Data on cerebral oxygenation was collected in both the intervention and the control group. The primary outcome was the reduction in the burden of cerebral hypo- and hyperoxia between the two groups. In this study we describe the associations between the burden of cerebral hypo- and hyperoxia, regardless of allocation to intervention or control group, and the biomarkers of brain injury from birth till term equivalent age that was collected as secondary and explorative outcomes in the SafeBoosC II trial.


METHODS
Cerebral oxygenation was continuously monitored during the first 72h of life in 166 extremely preterm infants. Cranial ultrasound was performed at day 1,4,7,14, and 35 and at term. Electroencephalogram (EEG) was recorded at 64h. Blood-samples taken at 6 and 64 hours were analysed for the brain injury biomarkers; S100beta, brain-fatty-acid-binding-protein, and neuroketal. All analyses were conducted post hoc.


RESULTS
Significantly more infants with a cerebral burden of hypoxia within the 4th quartile versus infants within quartile 1-3 were diagnosed with severe intracranial haemorrhage (11/39 versus 11/117, p = 0.003), had low burst rate on EEG (12/28 versus 21/103, p = 0.015), or died (14/41 versus 18/123, p = 0.006), whereas none of these events were significantly associated with cerebral hyperoxia. The blood biomarkers were not significantly associated with the burden of cerebral hypo- or hyperoxia.


CONCLUSIONS
The explorative analysis showed that early burden of cerebral hypoxia, but not hyperoxia was significantly associated with low brain electrical activity and severe intracranial haemorrhage while none of the three blood biomarkers were associated with the burden of either cerebral hypo- or hyperoxia.
Department of Neonatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Anne M
AM
Plomgaard
University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Thomas
T
Alderliesten
Rosie Hospital Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
Topun
T
Austin
University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Frank
F
van Bel
University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Manon
M
Benders
Department of Neonatology, Hospices Civils de Lyon, Claude Bernard University, Lyon, France.
Olivier
O
Claris
INFANT Centre, University College Cork, Cork, Ireland.
Eugene
E
Dempsey
NICU,Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
Monica
M
Fumagalli
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Christian
C
Gluud
Clinic of Neonatology, University of Zurich, Zurich, Switzerland.
Cornelia
C
Hagmann
Department of Neonatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Simon
S
Hyttel-Sorensen
University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands.
Petra
P
Lemmers
Haemoscan B.V., Groningen, The Netherlands.
Wim
W
van Oeveren
Department of Neonatology, La Paz University Hospital, Madrid, Spain.
Adelina
A
Pellicer
Research Unit on Brain Injury Neurorehabilitation Copenhagen, Department of Neurorehabilitation, TBI Unit, Rigshospitalet, Copenhagen University Hospital, Hvidovre, Denmark.
Tue H
TH
Petersen
Department of Pediatrics, Research Unit for Neonatal Micro- and Macrocirculation, Medical University of Graz, Graz, Austria.
Gerhard
G
Pichler
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Per
P
Winkel
Department of Neonatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Gorm
G
Greisen
D015415:Biomarkers / Q000378:metabolism*; D001930:Brain Injuries / Q000175:diagnosis* / Q000378:metabolism*; D004569:Electroencephalography / Q000379:methods; D005260:Female; D005865:Gestational Age; D006801:Humans; D018496:Hyperoxia / Q000175:diagnosis* / Q000378:metabolism*; D002534:Hypoxia, Brain / Q000175:diagnosis* / Q000378:metabolism*; D062071:Infant, Extremely Premature / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D008991:Monitoring, Physiologic / Q000379:methods; D010092:Oximetry / Q000379:methods; D010100:Oxygen / Q000378:metabolism; D019265:Spectroscopy, Near-Infrared / Q000379:methods
D015415:Biomarkers; D010100:Oxygen