Abstract:
Systemic hypothermia remains the only clinically proven effective neuroprotective strategy in global cerebral ischemia. However, due to the limited cooling efficiency and related systemic side effects in awake acute ischemic stroke (AIS) patients, its clinical translation has so far failed. Intra-arterial cold infusion (IACI) has emerged as an efficient strategy for selective brain cooling with fewer systemic impacts and easy integration into the up-to-date endovascular treatment (EVT) of AIS. Furthermore, the enormous neuroprotective effects of IACI were reported by a limited number of animal studies. Nevertheless, previously reported IACI approaches inevitably incurred delays of recanalization or interruption of cooling, potentially compromising the benefits brought by reperfusion or hypothermia. In this study, we put forward the strategy of continuous intra-carotid artery cold fluid Infusion (ICCI, ice-cold saline) via guide catheter, enabling much earlier hypothermia induction and sustained local hypothermia throughout the whole EVT procedure.
In experimental part I, we successfully simulated this approach in Sprague–Dawley rats subjected to filamental middle cerebral artery occlusion (MCAo) with our newly developed infusion port and modified cooling system. Under direct brain temperature monitoring, the cooling performance of ICCI was systematically evaluated, and a reproducible infusion protocol was established accordingly. Using this protocol, mild local hypothermia (~35°C) was achieved before reperfusion and deeper hypothermia (32–33°C) after reperfusion. In experimental Part II, the neuroprotective effects of continuous pre- to post-reperfusion ICCI were evaluated in rats subjected to 100-minute MCAo. At 24 hours post-treatment, infarct volume and brain edema were assessed using 2% 2, 3, 5 - triphenyltetrazolium chloride (TTC) stanning, and neurofunction was also evaluated. Physiological parameters (core body temperature, heart rate, mean arterial pressure, and reginal cerebral blood flow) as well as blood parameters were also measured. In the comparison of absolute infarct volume, extent of brain edema and neurofunction, no treatment effects were detected. However, post hoc analysis suggested potential neuroprotection of ICCI in rats with moderate ischemic injury.
To further test this hypothesis, serial MRI scanning was applied in experimental part III to dynamically evaluate individual infarct growth in 2-week survival groups, with scans performed after MCAo (before ICCI) , at 24 hours, and at 2 weeks post-treatment. Neurofunctional integrity, brain edema, and hemorrhagic transformation were also assessed. The results suggest that ICCI significantly inhibit cortical infarct growth. Regarding safety, ICCI under the current infusion protocol had minor impact on core body temperature, blood gases compared with systemic intravenous cold infusion. However, it was associated with transient reduction of mean arterial pressure and regional cerebral blood flow. More cases of hemorrhagic transformation were also observed in ICCI-treated rats compared with controls (5/11 rats versus 2/10 rats) on 2-week T2-MRI.
The present study highlights the great translational potential of continuous pre- to post-reperfusion ICCI via guide catheter for neuroprotection during EVT in AIS. Using our experimental setup, this clinical scenario can be easily simulated in MCAo rodents, which could be useful for future small animal ICCI studies to further confirm ICCI-mediated neuroprotective effects in AIS and optimize treatment variables for better neuroprotection. Under the current infusion protocol, the neuroprotective effects of ICCI were limited in the cortex after shorter ischemia duration (60 minutes), implying that patients with larger malignant infarctions should be excluded in future clinical pilot studies. The potential impact on regional cerebral blood flow and risk of hemorrhagic transformation should be further studied.
ischemic stroke