Hyperoxic Reperfusion After Global Ischemia Decreases Hippocampal Energy Metabolism

Abstract

Background and Purpose-Previous reports indicate that compared with normoxia, 100% ventilatory O 2 during early reperfusion after global cerebral ischemia decreases hippocampal pyruvate dehydrogenase activity and increases neuronal death. However, current standards of care after cardiac arrest encourage the use of 100% O 2 during resuscitation and for an undefined period thereafter. Using a clinically relevant canine cardiac arrest model, in this study we tested the hypothesis that hyperoxic reperfusion decreases hippocampal glucose metabolism and glutamate synthesis. Methods-After 10 minutes of cardiac arrest, animals were resuscitated and ventilated for 1 hour with 100% O 2 (hyperoxic) or 21% to 30% O 2 (normoxic). At 30 minutes reperfusion, [1-13 C]glucose was infused, and at 2 hours, brains were rapidly removed and frozen. Extracted metabolites were analyzed by 13 C nuclear magnetic resonance spectroscopy. Results-Compared with nonischemic controls, the hippocampi from hyperoxic animals had elevated levels of unmetabolized 13 C-glucose and decreased incorporation of 13 C into all isotope isomers of glutamate. These findings indicate impaired neuronal metabolism via the pyruvate dehydrogenase pathway for carbon entry into the tricarboxylic acid cycle and impaired glucose metabolism via the astrocytic pyruvate carboxylase pathway. No differences were observed in the cortex, indicating that the hippocampus is more vulnerable to metabolic changes induced by hyperoxic reperfusion. Conclusions-These results represent the first direct evidence that hyperoxia after cardiac arrest impairs hippocampal oxidative energy metabolism in the brain and challenge the rationale for using excessively high resuscitative ventilatory O 2 .

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

“…Hypoxia and/or ischemia may both lead to inadequate supplies of glucose and oxygen, followed by dose-dependent depletions of high-energy phosphates (2). Hyperoxic reoxygenation further impairs the oxidative energy metabolism in subregions of the brain (33). In line with these findings, our group has shown a slower decline in Krebs cycle intermediates in newborn pigs exposed to hypoxia followed by reoxygenation with 100% O 2 (34).…”

Post–Cardiac Arrest Syndrome

“…50 Although resumption of oxygen and metabolic substrate delivery at the microcirculatory level is essential, a growing body of evidence suggests that too much oxygen during the initial stages of reperfusion can exacerbate neuronal injury through production of free radicals and mitochondrial injury (see section on oxygenation). 51,52 Beyond the initial reperfusion phase, several factors can potentially compromise cerebral oxygen delivery and possibly secondary injury in the hours to days after cardiac arrest. These include hypotension, hypoxemia, impaired cerebrovascular autoregulation, and brain edema; however, human data are limited to small case series.…”

“…Although it is important to ensure that patients are not hypoxemic, a growing body of preclinical evidence suggests that hyperoxia during the early stages of reperfusion harms postischemic neurons by causing excessive oxidative stress. 51,52,143,144 Most relevant to post-cardiac arrest care, ventilation with 100% oxygen for the first hour after ROSC resulted in worse neurological outcome than immediate adjustment of the FIO 2 to produce an arterial oxygen saturation of 94% to 96%. 145 On the basis of preclinical evidence alone, unnecessary arterial hyperoxia should be avoided, especially during the initial post-cardiac arrest period.…”

Effect of Hypoxia and Hyperoxia on Cerebral Blood Flow, Blood Oxygenation, and Oxidative Metabolism

“…A few studies reported findings similar to ours. For example, Richards et al, (2007) measured O 2 metabolism in beagles using a 13 C NMR method and found that hyperoxia treatment after ischemia reduced O 2 metabolism. Working with a rat model, Harik et al, (1995) measured glucose metabolism with a 2-deoxyglucose method and observed that hypoxia with 10% FiO 2 increased glucose metabolism by 10% to 40%.…”