Focal cooling of brain parenchyma in a transient large vessel occlusion model: proof-of-concept

Abstract

IntroductionThe neuroprotective benefit of therapeutic hypothermia (TH) has been demonstrated, but systemic side effects and time required to achieve effective TH in acute ischemic stroke (AIS) care limits clinical use. We investigate rapid and localized cooling using a novel insulated catheter in an ischemia-reperfusion model.MethodsIn phase I (n=4), cold saline was delivered to the canine internal carotid artery via an insulated catheter. Temperature was measured using intracerebral thermocouples. The coolant flow rate was varied to meet a target temperature of 31–32°C in the hemisphere infused. In phase II (n=8), a temporary middle cerebral artery occlusion was created. Five dogs underwent localized TH at the optimal flow rate from phase I, and the remaining animals were untreated controls. Cooling was initiated 5 min before recanalization and continued for an additional 20 min following 45 min of occlusion duration. The outcome was infarct volume and neurological function.ResultsIpsilateral tissue cooling rates were 2.2±2.5°C/min at a flow rate of 20–40 mL/min with an observed minimum of 23.8°C. Tissue cooling was localized to the ipsilateral side of the infusion with little impact on temperatures of the core or contralateral hemisphere of the brain. In phase II, animals tolerated TH with minimal systemic impact. Infarct volume in treated animals was 0.2±0.2 cm3, which was smaller than in sham animals (3.8±1.0 cm3) as well as six untreated historical control animals (4.0±2.8 cm3) (p=0.013).ConclusionsProof-of-concept data show that localised brain TH can be quickly and safely achieved through a novel insulated catheter. The small infarct volumes suggest potential benefit for this approach.

Selective Brain Hypothermia in Acute Ischemic Stroke: Reperfusion Without Reperfusion Injury

“…For instance, a brain temperature reduction of more than 3.5 • C in 10 min was shown in a large pig model with SEBC using the direct intraarterial cold infusion (IACI) method (75). In a canine transient occlusion model, a reduction in brain temperature of >10 • C within 10 min was found using SEBC, with direct IACI during the phases of ischemia and post-reperfusion (76). The animals with brain cooling had smaller infarct sizes compared to controls.…”

Intra-arterial Cold Saline Infusion in Stroke: Historical Evolution and Future Prospects

“…A recent study by Caroff and colleagues was one of the first large animal studies to evaluate the optimal flow rate to balance cooling rate with judicious fluid administration [53]. In a canine model, infusion of cold saline (4.5 °C) via the internal carotid artery at 22 ml/min for 25 minutes most effectively cooled the ipsilateral hemisphere while minimizing infusion volume.…”

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

“…The guide catheter, however, is larger and could be sufficiently insulated. Heat-insulated guide catheter-like prototypes for ICCI have already been developed and successfully tested in healthy pigs [27] and in a canine stroke model [28]. Additionally, the larger lumen of the guide catheter would enable uninterrupted ICCI in parallel to EVT.…”

“…So far, continuous pre-to post-reperfusion intra-arterial cold infusion was successfully realized only in one canine [28] and one primate stroke model [35]. Use of large animal models might be more attractive when studying thermodynamic effects of ICCI due to their larger gyrencephalic brains compared with the small lissencephalic brains of rodents [5].…”