Targeting focal ischemic and hemorrhagic stroke neuroprotection: Current prospects for local hypothermia

Abstract

Therapeutic hypothermia (TH) has applications dating back millennia. In modern history, however, TH saw its importation into medical practice where investigations have demonstrated that TH is efficacious in ischemic insults, notably cardiac arrest and hypoxic‐ischemic encephalopathy. As well, studies have been undertaken to investigate whether TH can provide benefit in focal stroke (i.e., focal ischemia and intracerebral hemorrhage). However, clinical studies have encountered various challenges with induction and maintenance of post‐stroke TH. Most clinical studies have attempted to use body‐wide cooling protocols, commonly hindered by side effects that can worsen post‐stroke outcomes. Some of the complications and difficulties with systemic TH can be circumvented by using local hypothermia (LH) methods. Additional advantages include the potential for lower target temperatures to be achieved and faster TH induction rates with LH. This systematic review summarizes the body of clinical and preclinical LH focal stroke studies and raises key points to consider for future LH research. We conclude with an overview of LH neuroprotective mechanisms and a comparison of LH mechanisms with those observed with systemic TH. Overall, whereas many LH studies have been conducted preclinically in the context of focal ischemia, insufficient work has been done in intracerebral hemorrhage. Furthermore, key translational studies have yet to be done in either stroke subtype (e.g., varied models and time‐to‐treat, studies considering aged animals or animals with co‐morbidities). Few clinical LH investigations have been performed and the optimal LH parameters to achieve neuroprotection are unknown.

Blood biomarker changes following therapeutic hypothermia in ischemic stroke

“…It should be noted that we do not know whether the changes in these biomarkers originate in the brain or are due to a systemic effect of hypothermia. In the future, the isolation of neural‐specific extracellular vesicles/exosomes could be performed, especially in local hypothermia studies (Liddle et al., 2022 ). Additionally, the usefulness of monitoring some of these or other biomarkers during the early time points of hypothermia (e.g., during the first 24 h) to guide the clinical pivot to additional rescue therapies should also be investigated.…”

Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

“…In particular, many studies implied that a large volume of ICH was correlated with the severity and progression of PHE [ 115 , 116 , 138 , 139 ]. Probably due to the ambiguous effects of fever on ICH outcomes, the effects of therapeutic hypothermia on brain edema are currently heterogeneous in patients with ICH [ 123 , 140 , 141 ]. In addition to the demographic and imaging variables discussed above, other clinical variables may also influence the evolution of PHE after ICH.…”

“…Higher glucose [115] Larger initial ICH volume [116,138] Higher admission hematocrit [21] History of hypertension [138] Irregular hematoma or black hole sign [115,116] Higher admission time for partial thromboplastin time [21] Higher admission SBP [144,145] Larger initial EED [115] Absence in warfarin preuse [99,149] Impaired blood pressure regulation [139] Time from symptom onset [138] Higher serum levels of IL-6 and soluble CD163 [150,153] Higher body temperature [123,124,138,140,141] Absence in sulfonylurea drug pretreatment [142,143] Higher serum MMP-3 or MMP-8 levels [151,152] Abbreviations: PHE: perihematomal edema; APOE4: apolipoprotein E; AQP4: aquaporin 4; TIMP-2: tissue inhibitor of metalloproteinases 2; Hp: haptoglobin; SBP: systolic blood pressure; ICH: intracerebral hemorrhage; EED: edema extension distance; MMP: matrix metallopeptidase; AIVF: absent in ipsilateral venous filling; JVR: jugular vein reflex; CVFV: cerebral venous outflow volume. Oxidative Medicine and Cellular Longevity rPHE in patients with ICH [139].…”

A systematic review and meta-analysis on the efficacy of glibenclamide in animal models of intracerebral hemorrhage

“…Importantly, although pathophysiological characteristics overlap between ischemic and hemorrhagic stroke, putative treatments that work in one subtype must still be rigorously assessed in the other. Indeed, there are many therapies that work in pre-clinical ischemic stroke models, but give far less impressive results in ICH (e.g., hypothermia [ 51 ]). Glibenclamide, which shows promise in ischemic stroke, may fall into this category.…”