Normoxic Ventilation After Cardiac Arrest Reduces Oxidation of Brain Lipids and Improves Neurological Outcome

Abstract

Background and Purpose-Increasing evidence that oxidative stress contributes to delayed neuronal death after global cerebral ischemia has led to reconsideration of the prolonged use of 100% ventilatory O 2 following resuscitation from cardiac arrest. This study determined the temporal course of oxidation of brain fatty acyl groups in a clinically relevant canine model of cardiac arrest and resuscitation and tested the hypothesis that postischemic ventilation with 21% inspired O 2, rather than 100% O 2, results in reduced levels of oxidized brain lipids and decreased neurological impairment. Methods-Neurological deficit scoring and high performance liquid chromatography measurement of fatty acyl lipid oxidation were used in an established canine model using 10 minutes of cardiac arrest followed by resuscitation with different ventilatory oxygenation protocols and restoration of spontaneous circulation for 30 minutes to 24 hours. Results-Significant increases in frontal cortex lipid oxidation occurred after 10 minutes of cardiac arrest alone with no reperfusion and after reperfusion for 30 minutes, 2 hours, and 24 hours (relative total 235-nm absorbing peak areasϭ7.1Ϯ0.7 SE, 17.3Ϯ2.7, 14.2Ϯ3.2, 16.1Ϯ1.0, and 14.0Ϯ0.8, respectively; nϭ4, PϽ0.05). The predominant oxidized lipids were identified by gas chromatography/mass spectrometry as 13-and 9-hydroxyoctadecadienoic acids (13-and 9-HODE). Animals ventilated on 21% to 30% O 2 versus 100% O 2 for the first hour after resuscitation exhibited significantly lower levels of total and specific oxidized lipids in the frontal cortex (1.7Ϯ0.1 versus 3.12Ϯ0.78 g 13-HODE/g wet wt cortex., nϭ4 to 6, PϽ0.05) and lower neurological deficit scores (45.1Ϯ3.6 versus 58.3Ϯ3.8, nϭ9, PϽ0.05). Conclusions-With a clinically relevant canine model of 10 minutes of cardiac arrest, resuscitation with 21% versus 100% inspired O 2 resulted in lower levels of oxidized brain lipids and improved neurological outcome measured after 24 hours of reperfusion. This study casts further doubt on the appropriateness of present guidelines that recommend the indiscriminate use of 100% ventilatory O 2 for undefined periods during and after resuscitation from cardiac arrest.

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

“…The finding that hippocampal 3-nitrotyrosine immunoreactivity measured by ELISA is elevated after hyperoxic but not normoxic resuscitation is consistent with results we obtained with 3-nitrotyrosine immunohistochemistry [14] and with the observation that hyperoxic resuscitation increases brain oxidized free fatty acyl groups in this model [15]. More importantly, the exacerbation of tyrosine nitration during early reperfusion by hyperoxic resuscitation is associated with worse neurologic outcome [15] and greater hippocampal cell death compared to that observed after normoxic resuscitation [14]. These relationships add to the body of evidence that protein tyrosine nitration contributes to a wide range of neuropathologies, including traumatic brain injury [30,31], focal ischemia [32], global ischemia [33,34], and neurodegenerative diseases [35,36].…”

“…3-Nitrotyrosine (NT) serves as a footprint of peroxynitrite formation, occurs within neurons during ischemic reperfusion [13], and is exacerbated by the presence of high inspired O 2 [14]. Considering our evidence that hyperoxic resuscitation after cardiac arrest worsens neurologic outcome, increases lipid oxidation, and elevates brain lactate levels [15], we tested the hypothesis that loss of PDHC enzyme activity is also promoted by hyperoxic, compared to normoxic, reperfusion. The results of this study support this hypothesis and also provide evidence that peroxynitrite mediates oxidative modification and inactivation of this enzyme during ischemic reperfusion.…”

“…Previous HPLC measurements of oxidized fatty acyl groups present in the brains of hyperoxic and normoxic resuscitated animals indicated that hyperoxic ventilation exacerbates postischemic oxidative modification of lipids [15]. To determine if hyperoxia also promotes protein oxidation, we measured levels of 3-nitrotyrosine immunoreactivity in the hippocampus and cortex of nonischemic animals and at 2 h reperfusion after hyperoxic or normoxic resuscitation.…”

“…The animal model used for these studies has been used extensively by us and others to study global cerebral ischemia and reperfusion [15][16][17][18][19][20]. Adult purebred female beagles weighing 10-15 kg were anesthetized initially with an intravenous injection of veterinary thiopental (8-12 mg/kg).…”

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

“…This is in contrast to the situation in ischemic brain injury, in which lipid peroxidation is thought to play a more central role in the neuron death (Traystman et al 1991;Chan 1996;Liu et al 1998). However, it is quite plausible that the peroxidative damage could impair functional recovery in surviving neurons.…”