Eubaric hyperoxemia and experimental cerebral infarction

Abstract

We explore three questions concerning arterial hyperoxygenation and focal ischemia. (1) Does greater benefit accrue with higher levels of arterial hyperoxemia? (2) Is the net effect of continuous (intraischemic plus postischemic) oxygen therapy toxic, or beneficial to middle cerebral artery infarction? (3) In view of free radical theories of reperfusion injury, does hyperoxia isolated to the reperfusion period damage tissue? Rats subjected to transient, focal, normothermic, normoglycemic ischemia were assessed at 2 weeks' survival. Arterial hyperoxygenation from 98.9 +/- 4.0 to 312.2 +/- 48.4mm Hg during ischemia improved (p < 0.05) neurological function, as did isolated reperfusion hyperoxemia, but treatment with continuous hyperoxemia both during and after ischemia yielded greatest benefit (p < 0.001). Cortical infarcts constituted 6.5 +/- 1.8% of the hemisphere at normoxia, but 2.3 +/- 0.9% at hyperoxic levels (p < 0.01). Hyperoxia isolated to the reperfusion period also reduced cortical necrosis, from 6.5% to 2.7 +/- 1.2%. However, continuous intraischemic and reperfusion hyperoxemia led to only 0.2 +/- 0.1% cortical necrosis (p = 0.0005). Increasing the degree of hyperoxemia did not augment the benefit. We conclude that (1) eubaric hyperoxemia improves neurological and neuropathological outcome, (2) continuous oxygen therapy offers the greatest benefit, and (3) reperfusion hyperoxemia is beneficial. The findings should allay clinical concerns regarding oxygen-induced reperfusion injury, and, by obviating hyperbaric chambers, encourage clinical trials studying arterial hyperoxemia in treating stroke.

Normobaric Hyperoxia Delays Perfusion/Diffusion Mismatch Evolution, Reduces Infarct Volume, and Differentially Affects Neuronal Cell Death Pathways after Suture Middle Cerebral Artery Occlusion in Rats

“…There is growing evidence that normobaric oxygen therapy (NBO) is a promising treatment strategy to improve outcome after acute ischemic stroke (Flynn and Auer, 2002;Kim et al, 2005;Singhal et al, 2002a, b). This study substantially extends these prior findings by evaluating different treatment durations, cell-death pathways as well as regional tissue susceptibility to ischemia in two different rat models of focal cerebral ischemia.…”

“…Oxygen therapy can enhance free radical formation that may promote lipid peroxidation, blood-brain barrier integrity breakdown, glutamate-induced excitotoxic cell death, neuroinflammation, and increase brain hemorrhage, particularly when combined with reperfusion (Aronowski et al, 1997;Dubinsky et al, 1995;Elayan et al, 2000;Kent et al, 2001;Kim et al, 2005;Mink and Dutka, 1995). Nevertheless, several experimental studies showed impressive reductions in stroke lesion volumes with normobaric hyperoxia (NBO) (Flynn and Auer, 2002;Kim et al, 2005;Miyamoto and Auer, 2000;Singhal et al, 2002a, b). Most importantly, hyperoxia salvaged ischemic brain tissue without increasing the risk of oxygen free-radical injury (Kim et al, 2005;Singhal et al, 2002b).…”

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

“…Our present findings demonstrating reduced hippocampal protein tyrosine nitration and retention of PDHC enzyme activity with normoxic resuscitation support the need for additional preclinical and clinical studies to resolve this issue. The concept that hyperoxia worsens oxidative tissue damage and neurologic outcome after acute brain injury may not, however, apply to other forms of injury, e.g., stroke and trauma, as evidence suggests that hyperoxia can under some circumstances be beneficial [73][74][75][76][77]. The time during which the brain is exposed to high O 2 can also determine whether hyperoxia is helpful or detrimental.…”

A Pilot Study of Normobaric Oxygen Therapy in Acute Ischemic Stroke

“…3 A recent in vivo electron paramagnetic resonance oximetry study has shown that NBO significantly increases ptiO 2 in "penumbral" brain tissue. 15 In rodents, NBO therapy during transient focal stroke attenuates diffusion-weighted MRI (DWI) abnormalities, stroke lesion volumes, and neurobehavioral outcomes 4,16,17 without increasing markers of oxidative stress. 16 Based on preclinical results, we conducted a pilot clinical study to examine the risks and benefits of NBO in stroke.…”