Cerebral autoregulation according to the degree of damage in ischemia-reperfusion brain injury

Abstract

Cardiac arrest (CA), one of the major causes of mortality worldwide, is characterized as no sign of blood circulation due to disruption of the heart’s mechanical activity. In particular, when blood supply is not provided promptly to the brain, it leads to cerebral vascular dysfunction, which leads to irreversible tissue damage. This injury is called post-CA brain injury and is directly related to the prognosis of resuscitated patients regarding post-CA syndrome. Hitherto, therapeutic hypothermia has been the standard management for patients with CA, but due to multiple drugs and massive devices, the prognosis is determined 72 hours after CA onset. It is important to evaluate brain injury early and accurately to withdraw futile prolongation treatment and achieve meaningful neurological recovery. Cerebral autoregulation (AR) is the ability to maintain consistent cerebral blood flow (CBF) despite extensive variation in arterial blood pressure through neurovascular unit interaction. When CBF is reduced below the accommodation range due to ischemia, cerebral AR is impaired and brain damage occurs. Depending on the level of AR impairment, brain damage can be classified into three stages: I, II, and III. Stage I brain damage is potentially reversible when managed with appropriate treatment. However, current prognostic modalities are used to filter out the patients in the incurable stage. Therefore, in this study, we aimed to investigate the feasibility of early prognostic discrimination using cerebral AR, and factors related to impaired cerebral AR. First, we established an ischemia-reperfusion brain injury animal model in which damage to the cerebral cortex was given differentially. To provide differential damage to the brain in Wistar rats, transient middle cerebral artery occlusion (tMCAO) was combined to a conventional CA animal model: the 4-vessel occlusion model. MCAO duration was set as 0, 15, 30, and 60 minutes. As a result, at 0.5, 24, 48, and 72 hours after surgery, brain injury severity and body weight decreased, while neurological dysfunction increased. In addition, we confirmed through histological analysis that cortical infarct volume and inflammatory response increased according to brain injury severity 72 hours after surgery. Second, we investigated impaired cerebral AR by brain injury severity in ischemia-reperfusion brain injury models. To evaluate cerebral AR, we measured the CBF before and after injecting 50mg/kg acetazolamide. The CBF image was obtained at 0.5, 24, 48, and 72 hours after surgery. As a result, impairment of cerebral AR became severe at 24 hours postoperatively according to brain injury severity. Furthermore, the 72-hour postoperative survival rate was determined by the degree of cerebral AR impairment. Finally, we investigated expression of cerebral AR-related factors (Rho-associated protein kinase II [ROCK2], myosin phosphatase target subunit [MYPT], and endothelial nitric oxide synthase [eNOS]) and inflammatory response (glial fibrillary acidic protein [GFAP]) and apoptosis (bcl-2 associated X protein [Bax] and b-cell lymphoma 2 [Bcl-2]) related factors in the ischemia-reperfusion brain injury models. To evaluate the expression of related factors the core region of brain injury was obtained at 24 and 72 hours after surgery through dissection. As a result, 24 hours after surgery, expression of ROCK2 and MYPT were decreased in the moderate and severe cortical injury groups compared to the sham group. In addition, there was no difference of eNOS expression among groups. At 72 hours postoperative, GFAP and Bax expression increased while Bcl-2 decreased according to brain injury severity. In conclusion, these results indicate that cerebral AR is impaired according to the brain injury severity at 24 hours, and is associated the 72-hour postoperative prognosis. This suggests the possibility of early prognosis prediction through cerebral AR.