Hypothermia is the most reliably effective neuroprotectant, and yet systemic complications limit application. A large body of animal data suggests that hypothermia is effective for focal cerebral ischemia, namely acute ischemic stroke. In order to apply hypothermia effectively, a selective approach is required to maximize the effect on the brain while minimizing systemic side effects. Due to poor transferability of promising findings in rodent models to human clinical trials for neuroprotection, the focus of this review is large animal gyrencephalic models. Unlike rodent data which favor mild hypothermia, the majority of large animal studies on selective hypothermia support moderate-to-deep hypothermia (<30°C). Cold blood perfusion produces the rapid rate of temperature reduction and depth of hypothermia required to produce meaningful neuroprotection. Further studies of selective hypothermia in acute ischemic stroke require attention to duration and rate of cooling to optimize the neuroprotection offered by this technique.

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After initial enthusiasm for mild therapeutic hypothermia (TH) treatment after brain injuries, including global cerebral ischemia after cardiac arrest, subsequent trials suggested similar benefit using only targeted temperature management (TTM), with fewer side effects. Globally, effective treatment of brain ischemia with TH has declined. Recent data suggest, however, that TH to 33°C may be superior to TTM. We review the background and rationale underlying TH and TTM. We present previously published data from our own laboratory that confirms TH to 33°C provides superior brain cytoprotection, compared to 35°C or 37°C, over a range of delays to treatment and several durations of TH. We illustrate that the treatment effect size of either or 35 is superior to 37, but the effect size difference between 33 and 35, although significant, is small. We estimate that to demonstrate the superiority of TTM over TH, a clinical trial would need between 3,000 and 9,000 patients depending on the desired treatment effect size. Our review and our own data suggest that TH to 33°C is superior to TTM to 36°C, but an extremely large clinical trial would be needed to demonstrate the difference.

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BACKGROUND AND PURPOSE: Cofilin-actin rods are covalently linked aggregates of cofilin-1 and actin. Under ischemic conditions, these rods have been observed in neuronal dendrites and axons and may contribute to the loss of these processes. Hypothermia (Hypo) and the 70 kD inducible heat shock protein (Hsp70) are both known to improve outcomes after stroke, but the mechanisms are uncertain. Here, we evaluated the effect of these factors on cofilin-actin rod formation in a mouse model of stroke. MATERIALS AND METHODS: Mice were subjected to distal middle cerebral artery occlusion (dMCAO) and treated with Hypo using a paradigm previously shown to be neuroprotective. We similarly studied mice that overexpressed transgenic (Tg) or were deficient knockout (Ko) in the inducible 70 kDa heat shock protein (Hsp70), also previously shown to be protective by our group and others. Cofilin-actin rod formation was assessed by histological analysis at 4 and 24 h after dMCAO. Its expression was analyzed in three different regions, namely, infarct core (the center of the infarct), middle cerebral artery (MCA) borderzone (the edge of the brain regions supplied by the MCA), and the ischemic borderzone (border of ischemic lesion). Ischemic lesion size and neurological deficits were also assessed. RESULTS: Both Hypo-treated and Hsp70 Tg mice had smaller lesion sizes and improved neurological outcomes, whereas Hsp70 Ko mice had larger lesion sizes and worsened neurological outcomes. Cofilin-actin rods were increased after stroke, but were reduced by therapeutic Hypo and in Hsp70 Tg mice. In contrast, cofilin-actin rods were increased in ischemic brains of Hsp70 Ko mice. CONCLUSIONS: Cofilin-actin rod formation was suppressed under the conditions of neuroprotection and increased under circumstances where outcome was worsened. This suggests that cofilin-actin rods may act to participate in or exacerbate ischemic pathology and warrants further study as a potential therapeutic target.

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In acute ischemic stroke patients, selective brain hypothermia is a promising concept aiming at a fast decrease of brain temperature and thus neuroprotection in the acute phase of ischemia. At the same time, the emergence of mechanical thrombectomy (MT) as an effective treatment in large-vessel occlusion opens the door for a combination of neuroprotective approaches in the frame of a neurovascular, catheter-based intervention. In this regard, intracarotid cooling is a very effective energetic approach, using the blood supply to the penumbra as a fast transport vector for heat exchange in affected brain regions. We review the state of development of a novel closed-loop cooling catheter, describing design-related as well as procedural aspects and presenting results from different theoretical and experimental studies. Finally, we compare the concept with two alternative methods: cold saline infusion and extracorporeal blood cooling. We focus on the combination with MT, considering the effect of different and variable perfusion rates on the final goal of a “cold reperfusion” at the time of blood flow restoration.

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BACKGROUND AND PURPOSE: Cerebral hypothermia is a known neuroprotectant with promising applications in the treatment of ischemic events. Although systemic cooling is standard in post-cardiac arrest care, the deleterious effects of whole-body cooling have precluded it from translation into a viable treatment option for acute ischemic stroke (AIS). Selective cerebral cooling has been proposed as a method to minimize these risks while granting the neuroprotection of therapeutic hypothermia in AIS. METHODS: In a porcine model (n = 3), the efficacy of selective retrograde cerebral cooling through the internal jugular vein was evaluated in the setting of complete cerebral circulatory arrest. Furthermore, a novel endovascular device and cooling system enabling selective retrograde cerebral cooling were studied in a normothermic perfused cadaver. RESULTS AND CONCLUSION: Neurologic assessment of animals receiving this therapy reflected substantial neuroprotection in animals undergoing both 15 min and 30 min of otherwise catastrophic complete cerebral circulatory arrest. The novel endovascular device and cooling system were validated in human anatomy, demonstrating successful cerebral cooling, and feasibility of this mechanism of selective retrograde cerebral cooling.

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Stroke accounts for a large proportion of global mortality and morbidity. Selective hypothermia, via intranasal cooling devices, is a promising intervention in acute ischemic stroke. However, prior to large clinical trials, preclinical studies in large animal models of ischemic stroke are needed to assess the efficacy, safety, and feasibility of intranasal cooling for selective hypothermia as a neuroprotective strategy. Here, we review the available scientific literature for evidence supporting selective hypothermia and make recommendations of a preclinical, large, animal-based, ischemic stroke model that has the greatest potential for evaluating intranasal cooling for selective hypothermia and neuroprotection. We conclude that among large animal models of focal ischemic stroke including pigs, sheep, dogs, and nonhuman primates (NHPs), cynomolgus macaques have nasal anatomy, nasal vasculature, neuroanatomy, and cerebrovasculature that are most similar to those of humans. Moreover, middle cerebral artery stroke in cynomolgus macaques produces functional and behavioral deficits that are quantifiable to a greater degree of precision and detail than those that can be revealed through available assessments for other large animals. These NHPs are also amenable to extensive neuroimaging studies as a means of monitoring stroke evolution and evaluating infarct size. Hence, we suggest that cynomolgus macaques are best suited to assess the safety and efficacy of intranasal selective hypothermia through an evaluation of hyperacute diffusion-weighted imaging and subsequent investigation of chronic functional recovery, prior to randomized clinical trials in humans.

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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.

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Therapeutic hypothermia (TH) is a potent neuroprotectant against multiple forms of brain injury, but in some cases, prolonged cooling is needed. Such cooling protocols raise the risk that TH will directly or indirectly impact neuroplasticity, such as after global and focal cerebral ischemia or traumatic brain injury. TH, depending on the depth and duration, has the potential to broadly affect brain plasticity, especially given the spatial, temporal, and mechanistic overlap with the injury processes that cooling is used to treat. Here, we review the current experimental and clinical evidence to evaluate whether application of TH has any adverse or positive effects on postinjury plasticity. The limited available data suggest that mild TH does not appear to have any deleterious effect on neuroplasticity; however, we emphasize the need for additional high-quality preclinical and clinical work in this area.

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Therapeutic hypothermia (TH) remains one of the few proven neuroprotective modalities available in clinical practice today. Although targeting lower temperatures during TH seems to benefit ischemic brain cells, systemic side effects associated with global hypothermia limit its clinical applicability. Therefore, the ability to selectively reduce the temperature of the brain while minimally impacting core temperature allows for maximizing neurological benefit over systemic complications. In that scenario, selective brain cooling (SBC) has emerged as a promising modality of TH. In this report, we reviewed the general concepts of TH, from systemic to selective brain hypothermia, and explored the different cooling strategies and respective evidence, including preclinical and clinical data. SBC has been investigated in different animal models with promising results, wherein organ-specific, rapid, and deep target brain temperature managements stand out as major advantages over systemic TH. Nevertheless, procedure-related complications and adverse events still remain a concern, limiting clinical translation. Different invasive and noninvasive methods for SBC have been clinically investigated with variable results, and although adverse effects were still reported in some studies, therapies rendered overall safe profiles. Further study is needed to define the optimal technique, timing of initiation, rate and length of cooling as well as target temperature and rewarming protocols for different indications.

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INTRODUCTION: Mechanical thrombectomy (MT) has dramatically improved the prognosis for acute ischemic stroke (AIS) patients. Despite high recanalization rates, up to half of the patients will not present a good neurological outcome after MT. Therapeutic hypothermia is perhaps the most robust neuroprotectant studied preclinically. MATERIALS AND METHODS: We explored various warming effects that can reduce the effectiveness or potency of selective hypothermia during AIS under conditions similar to actual clinical care. Four different selective hypothermia layouts were chosen. Layouts 1 and 2 used a single catheter without and with an insulated IV bag. Layouts 3 and 4 used two catheters arrange coaxially, without and with an insulated IV bag. Independent variables measured were IV bag exit temperature, catheter inlet temperature, and catheter outlet temperature at four different flow rates ranging from 8 to 25 ml/min over an infusion duration of 20 min. RESULTS: Dominant warming occurs along the catheter pathway compared to warming along the infusion line pathway, ranging from 66% to 72%. Coaxial configurations provided an approximate 4°C cooler temperature benefit on delivered infusate over a single catheter. Brain tissue temperature predictions show that the maximum cooling layout, Layout 4 at maximum flow provides a 1°C within 5 min. CONCLUSION: Significant rewarming effects occur along the infusate flow path from IV bag to site of injury in the brain. Previous selective hypothermia clinical work, using flow rates and equipment at conditions similar to our study, likely produced rapid but not deep tissue cooling in the brain (~ 1°C).

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