A System for Continuous Pre- to Post-reperfusion Intra-carotid Cold Infusion for Selective Brain Hypothermia in Rodent StrokeModels

Abstract

Intra-carotid cold infusion (ICCI) appears as a promising method for hypothermia-mediated brain protection from ischemic stroke. Recent clinical pilot studies indicate easy implementation of ICCI into endovascular acute ischemic stroke treatment. Current rodent ICCI-in-stroke models limit ICCI to the post-reperfusion phase. To establish a method for continuous ICCI over the duration of intra-ischemia to post-reperfusion in rodent stroke models, a novel system was developed. Eighteen male Sprague-Dawley rats were included. Intraluminal filament method was used for transient middle cerebral artery occlusion (MCAO). Normal saline (~ 0 °C) was delivered (≤ 2.0 mL/min) into the internal carotid artery via a customized infusion system without interruption during MCAO (intra-ischemia) to after filament withdrawal (post-reperfusion). Bilateral cortical and striatal temperatures were monitored. Hypothermia goals were a temperature reduction in the ischemic hemisphere by 2 °C prior to reperfusion and thereafter maintenance of regional brain hypothermia at ~ 32 °C limiting the administered ICCI volume to ½ of each rat’s total blood volume. During ischemia, maximum brain cooling rate was achieved with ICCI at 0.5 mL/min. It took 2 min to reduce ischemic striatal temperature by 2.3 ± 0.3 °C. After reperfusion, brain cooling was continued at 2 mL/min ICCI first (over 42 s) and maintained at 32.1 ± 0.3 °C at 0.7 mL/min ICCI over a duration of 15 ± 0.8 min. ICCI (total 12.6 ± 0.6 mL) was uninterrupted over the duration of the studied phases. First system that allows continuous ICCI during the phases of intra-ischemia to post-reperfusion in small animals for selective brain cooling and for investigations of other neuroprotective infusions.

Optimizing intra-arterial hypothermia scheme for acute ischemic stroke in an MCAO/R rat model

“…Cattaneo G et al reported a special intracarotid cooling catheter conceived for fast and selective brain cooling during endovascular thrombectomy in an ovine stroke model 17 . Wang Y and his colleagues introduced a dedicated infusion system for continuous pre- to post-reperfusion ICCI in rat stroke models 18 . Intracarotid infusion of cold saline had been suggested as a practicable and effective cooling method and was investigated in small animal experiments 15 .…”

“…Hypothetically, IAH has a neuroprotective effect and significantly reduces the incidence of side effects and complications related to TH, rendering it a more effective therapy for AIS. Some published studies on theoretical models hypothesized that perfusion of cold normal-saline (NS) through the carotid artery could quickly reduce the temperature of the local brain and produce a protective effect on ischemic brain tissue with minimal influence on the body temperature 16 , which has been recently tested experimentally in pre-clinical 17 , 18 and clinical studies 19 , 20 . Nevertheless, IAH is far from standardized or optimized, and it is likely that some parameters, such as different perfusate temperatures, flow rate, and duration, would affect local brain tissue and whole body temperatures, leading to significant differences in efficacy and safety.…”

Selective Brain Cooling: A New Horizon of Neuroprotection

“…It decreases ischemic cerebral tissue and core body temperatures by at least 2°C and 0.3°C, respectively ( 65 ). Local hypothermia caused by cold saline infusion helps reduce the infarct size and is more effective at the start of cooling prior to vessel recanalization ( 66 , 67 ).…”

“…A rodent stroke model showed that SBC successfully alleviated ischemic-reperfusion damage and improved functional outcomes. In cold saline infusion (i.e., 2.0 mL/min, approximately 50% of the physiological blood flow in the common carotid artery of rats) before, during, and after reperfusion, ipsilateral brain temperature was lower by 5.3 ± 1.8°C within an average of >42 s after flushing and injection than that at baseline ( 67 ). As a direct cooling modality in ischemia-related areas, this type of method has the advantage of selective and rapid cooling of the brain ( 79 ).…”

“…Local hypothermia caused by cold saline infusion helps reduce the infarct size and is more effective at the start of cooling prior to vessel recanalization (66,67). SBC can also be achieved through intra-arterial infusions via a micro-catheter during mechanical thrombectomy (46).…”