Perinatal asphyxia remains one of the major causes of perinatal mortality and morbidity worldwide. Mild therapeutic hypothermia reduces brain injury after perinatal asphyxia. There is an ongoing search for strategies to further improve outcome, including best practice resuscitation and interventions that can be used in combination with hypothermia. The use of supplemental oxygen during resuscitation causes a number of harmful effects including increased cerebral injury. It is not known whether hypothermic neuroprotection can be improved by avoiding supplemental oxygen during resuscitation.
In this work, in vitro neurons, neonatal rats and newborn pigs were used as experimental models to study the effect of hyperoxic reoxygenation on hypothermic neuroprotection after perinatal asphyxia. A neuroprotective effect of therapeutic hypothermia was confirmed in all three models. Also, pigs treated with hypothermia had less expression of DNA repair enzymes. Hyperoxic reoxygenation resulted in a significant overshoot in oxygen tension in the piglet brain. Increased injury following hyperoxic reoxygenation was evident only in the rat model, where reoxygenation in 100% O2 increased brain injury and worsened neurological performance. Hypothermia reduced brain injury in the rat both after reoxygenation in air and in 100% O2, but hypothermia after 100% O2 gave no net protection. The results indicate that the neuroprotective effect of hypothermia is counteracted by using 100% O2 during reoxygenation. Thus, one way to optimise outcome after perinatal asphyxia is to avoid supplemental oxygen during resuscitation before therapeutic hypothermia.
This thesis supports the combined use of the two recommendations in the new international resuscitation guidelines: to use therapeutic hypothermia for hypoxic-ischaemic encephalopathy, and to use air for resuscitation if supplemental oxygen can be avoided.
List of papers. Papers I and III are removed from the thesis due to copyright restrictions.
Paper I: Dalen ML, Frøyland E, Saugstad OD, Mollnes TE, Rootwelt T. Post-hypoxic hypothermia is protective in human NT2-N neurons regardless of oxygen concentration during reoxygenation. Brain Res. 2009, 1259, 80-89. doi:10.1016/j.brainres.2008.12.055
Paper II: Dalen ML, Alme TN, Munkeby BH, Løberg EM, Pripp AH, Mollnes TE, Rootwelt T, Saugstad OD. Early protective effect of hypothermia in newborn pigs after hyperoxic, but not after normoxic, reoxygenation. J. Perinat. Med. 2010, 38, 545-556. doi:10.1515/JPM.2010.081
Paper III: Dalen ML, Alme TN, Bjørås M, Munkeby BH, Rootwelt T, Saugstad OD. Reduced expression of DNA glycosylases in post-hypoxic newborn pigs undergoing therapeutic hypothermia. Brain Res. 2010, 1363, 198-205. doi:10.1016/j.brainres.2010.09.080
Paper IV: Dalen ML, Liu XL, Elstad M, Brown E, Løberg EM, Saugstad OD, Rootwelt T, Thoresen M. Resuscitation with 100% oxygen counteracts the neuroprotective effect of therapeutic hypothermia in the neonatal rat. Manuscript. Pediatric Research (2012); 71 3, 247–252. doi:10.1038/pr.2011.43