Background and Purpose— Induction of hypothermia as a stroke therapy has been limited by logistical challenges. This study was designed to determine the hypothermic and neuroprotective efficacy of infusing cold saline directly into the internal jugular (IJ) vein and compare the effects of IJ hypothermia to those achieved by intracarotid artery hypothermia in an ischemic stroke model. Methods— The right middle cerebral artery was occluded in rats using an intraluminal filament. Immediately following reperfusion, hypothermia was achieved by infusing isotonic saline through microcatheter into the right IJ or right intracarotid over 30 minutes. Infarct sizes, neurological deficits, blood-brain barrier damage, edema volume, blood-brain barrier associated molecules (MMP-9 [matrix metallopeptidase 9] and AQP-4 [aquaporin 4]), and apoptosis-associated proteins (Bcl-2 and cleaved Caspase-3) were measured. Results— We found that both IJ- and intracarotid-based infusion cooled the brain robustly with a minimal effect on rectal temperatures. This brain cooling led to significantly reduced infarct volumes at 24 hours after reperfusion, as well as decreased expression of the proapoptotic protein cleaved Caspase-3 and increased expression of the antiapoptotic protein Bcl-2. Intracarotid and IJ cooling also aided in blood-brain barrier maintenance, as shown by decreased edema volumes, reduced Evans Blue leakage, and decreased expression of edema-facilitating proteins (MMP-9 and AQP-4). Both cooling methods then translated to preserved neurological function as determined by multiple functional tests over a 28-day observation period. Most importantly, the cooling and neuroprotective efficacy of IJ cooling was comparable to intracarotid cooling by almost every metric evaluated. Conclusions— Compared with intracarotid infusion, IJ infusion conferred a similar degree of hypothermia and neuroprotection following ischemic stroke. Given the ease of establishing vascular access via the internal jugular vein and the powerful neuroprotection that hypothermia provides, IJ brain cooling could be used as a promising hypothermia-induction modality going forward.
Background and Purpose— Nonhuman primates are increasingly used in translational studies of ischemic stroke. However, current scoring systems in monkeys (eg, Nonhuman Primate Stroke Scale) do not focus on impairments in activities of daily living, so clinically relevant data are scarce for evaluating functional deficits in this model. Methods— Here, we referenced the modified Rankin Scale to provide a primate version of Rankin Scale (pRS) for ranking neurological dysfunction in monkeys following stroke. We selected hand function and strength, level of activity, and general mobility as the main components of pRS. We also analyzed interobserver variability. Results— pRS is a simple scale with only 6 levels. Functional deficit can be easily classified into none (category 0), slight (categories 1–2), moderate (category 3–4), and severe disabilities (category 5) based on pRS. We validated this scoring system on 11 monkeys, all with varying levels of neurological dysfunction following stroke, assessed by blinded testers. After a short training period, both technicians and neurology residents were able to achieve a high level of consistency using this scoring system. Conclusions— pRS is a simple and reliable functional scale, similar to the widely used modified Rankin Scale, for evaluating long-term neurological dysfunction in nonhuman primates. We recommend further validation studies and analyses.
Stroke is the second leading cause of death globally and the third leading cause disability. Acute ischemic stroke (AIS), resulting from occlusion of major vessels in the brain, accounts for approximately 87% of strokes. Despite this large majority, current treatment options for AIS are severely limited and available to only a small percentage of patients. Therapeutic hypothermia (TH) has been widely used for neuroprotection in the setting of global ischemia postcardiac arrest, and recent evidence suggests that hypothermia may be the neuroprotective agent that stroke patients desperately need. Several clinical trials using systemic or selective cooling for TH have been published, reporting the safety and feasibility of these methods. Here, we summarize the major clinical trials of TH for AIS and provide recommendations for future studies.
Acute ischemic stroke (AIS) is a perpetual threat to life and functionality due to its high morbidity and mortality. In the past several decades, therapeutic hypothermia has garnered interest as an effective neuroprotective method in the setting of AIS. However, traditional hypothermic methods have been criticized for their low cooling efficiency and side effects. Intra-arterial cold saline infusion (IA-CSI), as a novel hypothermic method, not only minimizes these side effects, but is also perfectly integrated with widely accepted recanalization modalities in AIS, thereby serving as a promising prospect for clinical translation. In this article, we review the historical development of IA-CSI, summarize major studies of IA-CSI in rodents, large animals, and humans to date, and suggest insight into future development prospects in the field of AIS. We hope that this article will provide inspiration for the future application of hypothermia in AIS patients.
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