Hyperoxia Therapy in Cerebral Ischemia

Given the fate of neural tissue during cerebral ischaemia is critically determined by oxygen supply, hyperoxia therapy has emerged as a potential neuroprotective strategy. By elevating arterial oxygen content under normobaric or hyperbaric conditions, hyperoxia can reduce infarct volume, preserve the penumbra and stabilise the blood–brain barrier while modulating inflammatory and apoptotic pathways. Preclinical studies demonstrate that prompt administration of high‐fraction inspired oxygen can attenuate ischaemic injury via enhanced tissue oxygen tension, inhibition of NADPH oxidase–mediated oxidative stress and suppression of matrix metalloproteinase activity. Clinical investigations have explored both continuous high‐flow normobaric oxygen and adjunctive techniques such as oxygen‐loaded microbubbles combined with ultrasound‐stimulated sonoperfusion, aiming to bridge patients to reperfusion therapies. Despite promising reductions in lesion growth and improved neurological outcomes, concerns remain regarding optimal timing, dosage, potential vasoconstriction and free radical generation. Ongoing research seeks to refine delivery methods, identify patient subgroups most likely to benefit and integrate hyperoxia with recanalisation approaches to improve long‐term functional recovery.

Research from Nature Portfolio

Recent work has established circulating biomarkers of early blood–brain barrier disruption as both mechanistic insights and clinical tools. One seminal report demonstrated that ischaemia‐induced proteolysis of tight‐junction protein occludin leads to the release of discrete occludin fragments into the bloodstream. Blood occludin levels rise sharply within hours of arterial occlusion, closely mirroring the onset of barrier leakage and microvascular compromise. This finding not only elucidates a direct link between hyperoxia’s potential to preserve tight‐junction integrity and barrier function but also offers a rapid, minimally invasive indicator of haemorrhagic risk prior to reperfusion therapy.

Hyperoxia Therapy in Cerebral Ischemia publication trend

The graph below shows the total number of articles in hyperoxia therapy in cerebral ischemia across all publications each year (not limited to Nature Index journals).

Technical terms

Penumbra: The region of hypoperfused but still viable brain tissue surrounding the ischaemic core during stroke.

Tight junctions: Protein complexes between endothelial cells that regulate blood–brain barrier permeability.

Normobaric hyperoxia: Administration of high‐fraction inspired oxygen at standard atmospheric pressure.

Sonoperfusion: Enhancement of microvascular blood flow via ultrasound‐mediated cavitation, often combined with microbubbles.

Matrix metalloproteinases (MMPs): Enzymes that degrade extracellular matrix components, implicated in blood–brain barrier breakdown.

References

1. Oxygen-loaded microbubble-mediated sonoperfusion and oxygenation for neuroprotection after ischemic stroke reperfusion. Biomaterials Research (2023).
2. Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial. International Journal of Stroke (2023).
3. Normobaric Hyperoxia (NBHO): An Adjunctive Therapy to Cerebrovascular Recanalization in Ischemic Stroke. Aging and Disease (2023).
4. Blood Occludin Level as a Potential Biomarker for Early Blood Brain Barrier Damage Following Ischemic Stroke. Scientific Reports (2017).
5. Normobaric hyperoxia protects the blood brain barrier through inhibiting Nox2 containing NADPH oxidase in ischemic stroke. Medical Gas Research (2011).
6. Does normobaric hyperoxia increase oxidative stress in acute ischemic stroke? A critical review of the literature. Medical Gas Research (2015).