Normobaric oxygen treatment in acute ischemic stroke: a clinical perspective

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Abstract

Acute ischemic stroke is a common and serious neurological disease. Oxygen therapy has been shown to increase oxygen supply to ischemic tissues and improve outcomes after cerebral ischemia/reperfusion. Normobaric hyperoxia (NBO), an easily applicable and non-invasive method, shows protective effects on acute ischemic stroke animals and patients in pilot studies. However, many critical scientific questions are still unclear, such as the therapeutic time window of NBO, the long-term effects and the benefits of NBO in large clinic trials. In this article, we review the current literatures on NBO treatment of acute ischemic stroke in preclinical and clinical studies and try to analyze and identify the key gaps or unknowns in our understanding about NBO. Based on these analyses, we provide suggestions for future studies.

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Most cited references 53

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A pilot study of normobaric oxygen therapy in acute ischemic stroke.

Christine Benner, Aneesh B Singhal, Ferdinando S Buonanno … (2005)

Therapies that transiently prevent ischemic neuronal death can potentially extend therapeutic time windows for stroke thrombolysis. We conducted a pilot study to investigate the effects of high-flow oxygen in acute ischemic stroke. We randomized patients with acute stroke (<12 hours) and perfusion-diffusion "mismatch" on magnetic resonance imaging (MRI) to high-flow oxygen therapy via facemask for 8 hours (n=9) or room air (controls, n=7). Stroke scale scores and MRI scans were obtained at baseline, 4 hours, 24 hours, 1 week, and 3 months. Clinical deficits and MR abnormalities were compared between groups. Stroke scale scores were similar at baseline, tended to improve at 4 hours (during therapy) and 1 week, and significantly improved at 24 hours in hyperoxia-treated patients. There was no significant difference at 3 months. Mean (+/-SD) relative diffusion MRI lesion volumes were significantly reduced in hyperoxia-treated patients at 4 hours (87.8+/-22% versus 149.1+/-41%; P=0.004) but not subsequent time points. The percentage of MRI voxels improving from baseline "ischemic" to 4-hour "non-ischemic" values tended to be higher in hyperoxia-treated patients. Cerebral blood volume and blood flow within ischemic regions improved with hyperoxia. These "during-therapy" benefits occurred without arterial recanalization. By 24 hours, MRI showed reperfusion and asymptomatic petechial hemorrhages in 50% of hyperoxia-treated patients versus 17% of controls (P=0.6). High-flow oxygen therapy is associated with a transient improvement of clinical deficits and MRI abnormalities in select patients with acute ischemic stroke. Further studies are warranted to investigate the safety and efficacy of hyperoxia as a stroke therapy.

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Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia.

Wenlan Liu, Jiangang Shen, Xu Qin … (2009)

Early blood-brain barrier (BBB) disruption resulting from excessive neurovascular proteolysis by matrix metalloproteinases (MMPs) is closely associated with hemorrhagic transformation events in ischemic stroke. We have shown that normobaric hyperoxia (NBO) treatment reduces MMP-9 increase in the ischemic brain. The aim of this study was to determine whether NBO could attenuate MMP-9-mediated early BBB disruption following ischemic stroke. Rats were exposed to NBO (95% O(2)) or normoxia (30% O(2)) during 90-min middle cerebral artery occlusion, followed by 3-hour reperfusion. NBO-treated rats showed a significant reduction in Evan's blue extravasation in the ischemic hemisphere compared with normoxic rats. Topographically, Evan's blue leakage was mainly seen in the subcortical regions including the striatum, which was accompanied by increased gelatinolytic activity and reduced immunostaining for tight-junction protein, occludin. Increased gelatinolytic activities and occludin protein loss were also observed in isolated ischemic microvessels. Gel gelatin zymography identified that MMP-9 was the main enzymatic source in the cerebral microvessels. Incubation of brain slices or isolated microvessels with purified MMP-9 revealed specific degradation of occludin. Inhibition of MMP-9 by NBO or MMP-inhibitor, BB1101, significantly reduced occludin protein loss in ischemic microvessels. These results suggest that NBO attenuates early BBB disruption, and inhibition of MMP-9-mediated occludin degradation is an important mechanism for this protection.

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Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke.

Eng Lo, Bruce R. Rosen, Aneesh B Singhal … (2002)

Hyperbaric oxygen therapy is considered an important stroke treatment strategy. To determine whether normobaric oxygen is neuroprotective, and, if so, what the therapeutic time window is. Experiment 1-Serial diffusion- and perfusion-weighted MRI (DWI and PWI) was performed after middle cerebral artery filament occlusion (MCAO) in rats randomized to FiO(2) 30% (normoxia) or FiO(2) 100% (hyperoxia). Experiment 2-48-hour lesion volumes were analyzed in rats subjected to 2-hour MCAO and randomized to normoxia or hyperoxia starting 15, 30, or 45 minutes after MCAO and ending 15 minutes after reperfusion. Experiment 1-Lesion apparent diffusion coefficient (ADC) values were persistently low in normoxic animals. In hyperoxia-treated rats, ADC values in cortical border zones showed progressive recovery from 66 +/- 3% of contralateral before hyperoxia, to 104 +/- 20% at approximately 2 hours. Striatal ADC values showed early but ill-sustained improvement. ADC lesion volumes increased progressively in the normoxia group. In the hyperoxia group, ADC lesion volumes tended to decrease after starting hyperoxia; however, lesions later increased in size, and 2-hour lesion volumes were not significantly different from baseline. PWI showed stable right MCA hypoperfusion in all animals. Experiment 2-Hyperoxia within 30 minutes significantly reduced total and cortical lesion volumes at 48 hours after stroke. Striatal lesion volumes were significantly reduced in the hyperoxia-15 group. In rats subjected to transient stroke, 100% oxygen administered within 30 minutes salvages ischemic brain tissue, especially in the cerebral cortex. Reducing the time to treatment enhances the degree of neuroprotection.

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Journal

Journal ID (nlm-ta): Med Gas Res

Journal ID (iso-abbrev): Med Gas Res

Journal ID (publisher-id): MGR

Title: Medical Gas Research

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Electronic): 2045-9912

Publication date Collection: Jul-Sep 2016

Publication date (Electronic): 14 October 2016

Volume: 6

Issue: 3

Pages: 147-153

Affiliations

[1 ]Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China

[2 ]Pediatric Intensive Care, First Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia Autonomous Region, China

[3 ]Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

Author notes

[* ]Correspondence to: Ke Jian Liu or Xun-ming Ji, kliu@ 123456salud.unm.edu or robertjixm@ 123456hotmail.com .

Author contributions

SHS reviewed the NBO studies in stroke, wrote up the manuscript. ZFQ and YML improved the structure. XMJ reviewed the NBO studies in clinic and edited the overall manuscript. KJL participated in the overall design of the review and obtained partial funding. All authors have read and approved the final version of this paper.

Author information

Xun-ming Ji http://orcid.org/0000-0002-6588-1617

Ke Jian Liu http://orcid.org/0000-0002-6588-1617

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Publisher ID: MGR-6-147

DOI: 10.4103/2045-9912.191360

PMC ID: 5110139

PubMed ID: 27867482

SO-VID: f719b0a2-a5c3-4167-9dbf-edb6853252d9

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Normobaric oxygen treatment in acute ischemic stroke: a clinical perspective

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Most cited references 53

A pilot study of normobaric oxygen therapy in acute ischemic stroke.

Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia.

Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke.

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