title: Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death.
abstract: Resuscitation and prolonged ventilation using 100% oxygen after cardiac arrest is standard clinical practice despite evidence from animal models indicating that neurologic outcome is improved using normoxic compared with hyperoxic resuscitation. This study tested the hypothesis that normoxic ventilation during the first hour after cardiac arrest in dogs protects against prelethal oxidative stress to proteins, loss of the critical metabolic enzyme pyruvate dehydrogenase complex (PDHC), and minimizes subsequent neuronal death in the hippocampus. Anesthetized beagles underwent 10 mins ventricular fibrillation cardiac arrest, followed by defibrillation and ventilation with either 21% or 100% O2. At 1 h after resuscitation, the ventilator was adjusted to maintain normal blood gas levels in both groups. Brains were perfusion-fixed at 2 h reperfusion and used for immunohistochemical measurements of hippocampal nitrotyrosine, a product of protein oxidation, and the E1alpha subunit of PDHC. In hyperoxic dogs, PDHC immunostaining diminished by approximately 90% compared with sham-operated dogs, while staining in normoxic animals was not significantly different from nonischemic dogs. Protein nitration in the hippocampal neurons of hyperoxic animals was 2-3 times greater than either sham-operated or normoxic resuscitated animals at 2 h reperfusion. Stereologic quantification of neuronal death at 24 h reperfusion showed a 40% reduction using normoxic compared with hyperoxic resuscitation. These results indicate that postischemic hyperoxic ventilation promotes oxidative stress that exacerbates prelethal loss of pyruvate dehydrogenase and delayed hippocampal neuronal cell death. Moreover, these findings indicate the need for clinical trials comparing the effects of different ventilatory oxygen levels on neurologic outcome after cardiac arrest.
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Vereczki
authors.forename: Erica
authors.initials: E
authors.lastname: Martin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Rosenthal
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.forename: Gloria E
authors.initials: GE
authors.lastname: Hoffman
authors.forename: Gary
authors.initials: G
authors.lastname: Fiskum
mesh_terms: D000818:Animals; D016887:Cardiopulmonary Resuscitation / Q000009:adverse effects* / Q000379:methods*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D006323:Heart Arrest / Q000628:therapy*; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D009474:Neurons / Q000473:pathology; D018384:Oxidative Stress; D010100:Oxygen / Q000627:therapeutic use*; D010102:Oxygen Inhalation Therapy / Q000379:methods; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D011768:Pyruvate Dehydrogenase Complex; C002744:3-nitrotyrosine; D014443:Tyrosine; D010100:Oxygen