The Efficacy of Normobaric Oxygen on Chronic Cerebral Ischemia
Condition: Normobaric Oxygen; Cerebral Ischemia
MeSH terms: Brain Ischemia; Cerebral Infarction; Ischemia
Study type: Interventional

Summary: 
      Chronic cerebral ischemia (CCI) is viewed as an alarming state induced by long-term reduction
      in cerebral perfusion, which is associated with neurological deficits and high risk of stroke
      occurrence or recurrence. CCI accounts for a large proportion in both outpatient and
      inpatient subjects with cerebrovascular disease, while the treatment of CCI remains a
      formidable challenge to clinicians. Normobaric oxygen (NBO) is an adjuvant hyper-oxygenation
      intervention supplied with one atmosphere pressure (1ATA=101.325kPa). A plethora of studies
      have demonstrated the efficacy of NBO on the penumbra in acute stroke. NBO has been shown to
      increase oxygen pressure, raise intracranial blood flow, protect blood-brain barrier and
      enhance neuro-protective effects. As the similar underlying mechanisms shared by the penumbra
      in stroke and the ischemic-hypoxic brain tissues in CCI, the investigators speculate that NBO
      may serve as a promising therapeutic strategy for attenuating short-term symptoms or
      improving long-term clinical outcomes amongst patients with CCI. Due to the scant research
      exploring the efficacy of NBO for treating CCI so far, the clinical studies are warranted to
      verify this hypothesis urgently.
    

Detailed description: 
      INTRODUCTION Chronic cerebral ischemia (CCI), which is firstly proposed by Japanese scholars
      in 1990s, is considered as a pathological status induced by persistent reduction of cerebral
      blood volume and flow (CBV and CBF), leading to ischemia and hypoxia in the brain tissue.
      Long-time ischemic-hypoxic injury can cause various atypical brain dysfunctions, such as
      headache, dizziness, cognitive decline and emotional abnormalities. Under the low-perfusion
      background, the brain tissue is more vulnerable to ischemic-hypoxic insult; thus, the
      incidence of ischemic events amongst individuals with CCI is substantially higher than those
      without. It has been reported that intracranial atherosclerotic stenosis (ICAS), internal
      jugular venous stenosis (IJVS) and cardiogenic cerebral circulation insufficiency are the
      common pathogenesis of CCI, with the hypoperfusion as a vital mechanism accounting for these
      clinical presentations.

      Normobaric oxygen (NBO) is a routine adjuvant hyperoxygenation intervention supplied by nasal
      cannula or facemask (such as Venturi mask), with one atmosphere pressure (1ATA=101.325kPa).
      Evidence available shows that NBO may be a safe, convenient and promising therapeutic
      strategy for multi-organ protection, which has garnered increasing attention of researchers
      over the past years. However, some studies do not support the favorite efficacy of NBO. For
      instance, a large meta-analysis conducted by Chu et al. revealed that in acutely ill adult
      patients, oxygen supplementation might increase mortality without improving patient-important
      outcomes. The negative results can contribute to acute critical conditions and some serious
      complications such as infection, arrhythmia and dyspnea. In contrast to previous experimental
      data confirming the NBO protection on acute stroke, a recent multi-center randomized clinical
      trial concludes that this oxygen supplement does not reduce the rate of death or disability.
      The incongruent conclusions between clinical and animal studies may be attributable to the
      protective mechanisms of NBO behind cerebral ischemia, the rationale for the protective
      effect afforded by NBO is freezing penumbra and extending the time window for reperfusion,
      meaning that NBO may be not applicable for patients with permanent vessel occlusion. Animal
      research has corroborated that NBO can reduce infarct size and improve post-stroke outcomes
      after thrombolysis in ischemic stroke, and a large multi-center randomized prospective trial
      is ongoing.

      Theoretically, low cerebral blood perfusion in CCI patients exposes the brain tissue to an
      ischemic-hypoxic condition, which is similar to that in penumbra in acute ischemic stroke.
      Therefore, given the prominent effectiveness in penumbra, NBO, which can supply abundant
      oxygen, may yield some benefits to the ischemic-hypoxic brain tissue in CCI patients.
      However, there is no study investigating the oxygen supplementation applied in CCI up to now.

      THEORY OF THE HYPOTHESIS

      The investigators' hypothesis is that NBO can enhance oxygen content in the ischemic-hypoxic
      brain tissue in CCI patients and subsequently improve both short-term symptoms and long-term
      clinical outcomes. The basis of the hypothesis is inferred by several convinced theories
      presented as follows:

        1. NBO is capable of increasing the arterial partial pressure of oxygen (pO2) and raising
           the dissolved oxygen fraction in the aorta and the smallest arterioles. In this regard,
           Liu et al. reported that after NBO treatment, the penumbral interstitial pO2 could be
           maintained close to pre-ischemic normal value. Given the fact that both penumbra in
           acute stroke and abnormal brain tissues in CCI are caused by ischemia and hypoxia, NBO
           may be conceived as an effective adjuvant therapy for CCI as well.

        2. NBO can increase CBF/CBV in the penumbra in acute stroke. During NBO treatment,
           vasodilation occurs in the ischemic regions, while the non-ischemic regions show
           vasoconstriction. The raised pO2 and increased blood flow in the penumbra are involved
           in down regulating zinc levels, which may contribute to the neuro-protective effect by
           NBO. Whereby, improving perfusion in the ischemic-hypoxic brain tissue can result in the
           relief of the associated clinical symptoms.

        3. NBO is able to attenuate blood brain barrier (BBB) disruption in cerebral ischemia,
           possibly through inhibiting matrix metalloproteinase-9 (MMP-9) mediated degradation of
           tight junction proteins. The integrity of BBB is influenced by various pathological
           processes, such as inflammatory mediators invasion, edema formation, and hemorrhagic
           transformation. Similarly, BBB protection provided by NBO may also be available to CCI
           patients so that the impaired brain functions may be at least partially restored, or
           delayed CCI-induced brain damage.

        4. Other underlying neuro-protective mechanisms, including reducing peri-infarct
           depolarizations, improving aerobic metabolism, preventing apoptotic cell death and
           ameliorating inflammation can offer benefits to patients with cerebral ischemia. On the
           other hand, NBO is safe enough as it does not augment the formation of reactive oxygen
           species, nitrogen species and some other mediators implicated in the exacerbation of
           oxidative stress injury.

      Currently, there are very few reports in literature regarding the application of NBO in CCI
      and this is undoubtedly a brand-new field that deserves more attention. Differ from the
      beneficial effects observed in experimental stroke models, most of the clinical trials failed
      to reach favorable results. As the investigator discussed aforementioned, the ischemic
      penumbra is a vital target for NBO and low rate of revascularization is responsible for the
      poor outcomes in acute stroke patients. CCI refers to a state of long-term reduction in
      cerebral perfusion secondary to ICAS, IJVS or other pathogeneses, meaning that most of the
      afflicted brain tissues are in ischemic-hypoxic conditions, just like the penumbra in acute
      stroke. This phenomenon suggests that supplying enough oxygen may hold the potential of
      enhancing the resistance of brain tissues to hypoxic insults, slowing down the deterioration
      and preventing secondary ischemic stroke in CCI patients. Meanwhile, rapid oxygen content
      enhancement enables immediate improvements in ischemic-hypoxic conditions, allowing for the
      relief of clinical symptoms in a short period of time.

      IMPLICATIONS OF THE HYPOTHESIS In real clinical practice, there are a large number of
      patients suffering from CCI and the current mainstay therapeutic strategies are far from
      satisfactory. Conservative therapies mainly involve anti-platelets, lipid-lowering agents and
      neuro-protectives, but their effectiveness is still uncertain. The efficacy of endovascular
      treatment, such as endarterectomy and intravascular stenting, is still controversial and
      should not be considered superior to the conservative treatment. Moreover, endovascular
      treatment may be not suitable for all patients with CCI. Recently, remote ischemic
      conditioning (RIC) has emerged as an innovative and promising adjunctive approach for
      multi-organ protection. It has been demonstrated that daily RIC can reduce the rate of stroke
      recurrence and improve the long-term clinical outcomes in patients with CCI. However, it is
      reasonable to expect that RIC requires a longer time to take effect, thus patients cannot
      relieve their symptoms within a short period of time following treatment initiation.
      Meanwhile, there is still a portion of patients who may not benefit from or be
      contraindicated to RIC. According to available evidence and the hypothesis, NBO is able to
      enhance the oxygen content of ischemic regions, increase cerebral perfusion, and prevent
      brain tissues from secondary injury, all of which could help relieve the symptoms in a short
      time and improve the long-term clinical outcomes profoundly. Therefore, NBO may serve as a
      promising adjunctive alternative to current treatment strategies.

      CONCLUSION As NBO may profoundly improve both the short-term symptoms as well as the
      long-term clinical outcomes in CCI patients, it should be deemed as a brand-new effective and
      convenient adjuvant treatment strategy if the hypothesis is validated. Well-designed animal
      experiments and clinical trials are urgently warranted in the next step to corroborate the
      effectiveness of NBO on brain protection in patients with CCI.
    

Intervention name(s): normobaric oxygen; room air
Intervention type(s): Device; Device
Intervention description(s): Normobaric oxygen (NBO) is a routine adjuvant hyperoxygenation intervention supplied by facemask (such as Venturi mask), with one atmosphere pressure (1ATA=101.325kPa).; The patient had a rest with lying, sitting or walking, did not performed with NBO intervention.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: normobaric oxygen; cerebral ischemia; EEG