Hyperoxia- and hypercapnia-induced changes of cerebral blood flow and metabolic rate of oxygen in ischemic brain tissue

Background: Ischemic penumbra is defined as a hypoperfused brain tissue with preserved membrane potential and ion homestasis. Study of neurometabolic and neurovascular behavior of penumbral cells is essential to shed some light on the pathophysiology of stroke. Patients with stroke or occlusion of carotid artery demonstrate local or global decreases of oxygen tension. The ischemic brain tissue caused by the decline in oxygen tension undergoes certain metabolic changes which can result in apoptotic cell death. Improvement of tissue oxygenation in ischemic penumbra will therefore inhibit the degenerative process seen in the early stage of stroke. Objectives: The aim of the current study is to investigate whether whole brain cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF) could be manipulated by inhalation of oxygen and carbon dioxide which in turn could lead to a therapeutic means for ischemic tissue. Methods: We used positron emission tomography (PET) to measure CMRO2 and CBF in two groups of subjects i.e. patients with occlusion of carotid artery (n=6) and healthy controls (n=11). During the four 3-min CBF-PET scans the subjects inhaled a semirandom sequence of 100% O2 (hyperoxia), 5% CO2 (mild hypercapnia), carbogen (95% O2 + 5% CO2) or atmospheric air (baseline). The sequence was repeated for the measurements of CMRO2. Parametric subtraction maps (gas minus baseline) of CBF and CMRO2 for healthy group were calculated following coregistration of PET images to the corresponding anatomical MRI images (patient data is under completion). Results: Significant increases of CBF in the whole brain (compared to baseline) were observed when the subjects were given CO2 and carbogen (paired t-test; p-values: 0.0018 and 0.0042 accordingly) while a significant decrease in CBF was observed during the inhalation of pure oxygen (p-value: 0.0055). However, no significant changes in the global CMRO2 were observed following the inhalation of any of the three gases. The results also were confirmed by statistical cluster analysis. Arterial blood oxygen saturation (SaO2) significantly rose from baseline (97.2%) when oxygen and carbogen were applied (99.89% & 99.80% respectively). However, there was no significant difference between oxygen and carbogen potency in increasing SaO2. Discussion: Animal experiments have shown that either oxygen therapy or mild hypercapnia could reduce the final infarct volume (1). The present data demonstrate that inhalation of carbogen and CO2 increases CBF significantly in healthy brain tissue. Moreover, only carbogen was able to enhance the vital physiological factor such as SaO2. This implies that inhalation of carbogen is capable of optimizing oxygenation of brain tissue, a vital factor for tissue survival. Patients with stroke could be treated by thrombolysis during a 3-hour window. Improvement of brain tissue oxygenation during the pre-admission time has potential of reducing the tissue damage. The completion of our patient data will reveal whether it is possible to accomplish the same effect in ischemic tissue. If so, this will slow down the tissue degeneration which will eventually enable us to extend the 3-hour therapeutic window.