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

Even after reading the whole thing I have no clue.

Selective Brain Hypothermia in Acute Ischemic Stroke: Reperfusion Without Reperfusion Injury Jae H. Choi^1,2*, Sven Poli³, Michael Chen⁴, Thanh N. Nguyen⁵, Jeffrey L. Saver⁶, Charles Matouk⁷ and John Pile-Spellman^1,2

• ¹Neurovascular Center, Neurological Surgery, P.C., Lake Success, NY, United States
• ²Hybernia Medical, LLC, New Rochelle, NY, United States
• ³Department of Neurology & Stroke, Hertie-Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Tübingen, Germany
• ⁴Stroke Center, Department of Neurosurgery, Rush University Medical Center, Chicago, IL, United States
• ⁵Interventional Neurology/Neuroradiology, Boston University School of Medicine, Boston, MA, United States
• ⁶Comprehensive Stroke Center and Department of Neurology, University of California, Los Angeles (UCLA), Los Angeles, CA, United States
• ⁷Neurovascular Surgery, Department of Neurosurgery, Yale University-New Haven Hospital, New Haven, CT, United States

In acute ischemic stroke, early recanalization of the occluded artery is crucial for best outcome to be achieved. Recanalization aims at restoring blood flow to the ischemic tissue (reperfusion) and is achieved with pharmacological thrombolytic drugs, endovascular thrombectomy (EVT) devices, or both. The introduction of modern endovascular devices has led to tremendous anatomical and clinical success with rates of substantial reperfusion exceeding 80% and proven clinical benefit in patients with anterior circulation large vessel occlusions (LVOs). However, not every successful reperfusion procedure leads to the desired clinical outcome. In fact, the rate of non-disabled outcome at 3 months with current EVT treatment is ~1 out of 4. A constraint upon better outcomes is that reperfusion, though resolving ischemic stress, may not restore the anatomic structures and metabolic functions of ischemic tissue to their baseline states. In fact, ischemia triggers a complex cascade of destructive mechanisms that can sometimes be exacerbated rather than alleviated by reperfusion therapy. Such reperfusion injury may cause infarct progression, intracranial hemorrhage, and unfavorable outcome. Therapeutic hypothermia has been shown to have a favorable impact on the molecular elaboration of ischemic injury, but systemic hypothermia is limited by slow speed of attaining target temperatures and clinical complications. A novel approach is endovascular delivery of hypothermia to cool the affected brain tissue selectively and rapidly with tight local temperature control, features not available with systemic hypothermia devices. In this perspective article, we discuss the possible benefits of adjunctive selective endovascular brain hypothermia during interventional stroke treatment.

Introduction

Several randomized controlled clinical trials have demonstrated the clinical benefit of endovascular thrombectomy (EVT) in selected patients with acute ischemic stroke due to large vessel occlusions (LVO-AIS) (1–7). The introduction of endovascular clot extraction has not only led to tremendous improvements in reperfusion rates (often exceeding 80%) and clinical outcome (compared to intravenous rtPA alone), but also offered opportunities to further refine patient selection criteria and extend the treatment time window (8–10). Although a significant improvement in clinical outcome after LVO-AIS could be achieved, a wide gap remains between the success in restoring perfusion through the occluded artery (>4 out of 5) and the rate of excellent, non-disabled (modified Rankin Scale score 0-1) functional outcome achieved in only ~1 out of 4 treated patients (11). Recently, Van Horn and colleagues evaluated 123 consecutive patients at a single German center from 2015 to 2019 who had complete TICI (Thrombolysis in Cerebral Infarction score) 3 reperfusion and still found 54.5% to have poor clinical outcomes at 90 days (12).

Brain ischemia triggers a cascade of molecular and cellular mechanisms many of which have been identified (13). Following the quick depletion of oxygen and energy carriers from brain tissue it comes to progressive failure of cellular ion pumps, NMDA (N-Methyl- d-aspartate) receptor activation, and anoxic depolarization that further lead to disturbance of ion homeostasis, excitotoxicity, acidification, and increasing cellular influx of Ca2+ (14–17). Activation of nitric oxide synthase and cyclooxygenase-2, generation of free radicals, upregulation of cell adhesion molecules, and increase in the production of proinflammatory cytokines follow (18–22). The resulting inflammatory reactions include recruitment of cell-mediated immunity, activation of protein kinases and matrix zinc-metalloproteinases, and neutrophil transmigration, among others (22–28). In addition, apoptosis is promoted by up-regulation of the BAX (Bcl-2 Associated X-protein) and calpain genes (29, 30).

As a result of these molecular pathways, functional and structural changes follow, such as impaired vasomotor regulation (31, 32), cytotoxic and vasogenic edema (33, 34), and breakdown of the blood-brain-barrier (35–37). With sustained activation of these pathways the risk for extensive neuronal cell death, infarct progression, and intracranial hemorrhage increases (38, 39).

Paradoxically, reperfusion of the ischemic brain tissue can exacerbate these destructive processes that have been triggered by stroke. This is called reperfusion injury and is thought to be the result of multiple pathways of tissue insult, oxidative stress, leukocyte infiltration, complement activation, mitochondrial dysfunction, platelet activation and aggregation, and blood-brain-barrier disruption, culminating in neuron death, brain edema or hemorrhagic transformation (13, 40–42). Reperfusion injury is a common biologic phenomenon across multiple organs and not limited to reperfusion procedures of the neurovasculature, also occurring following treatment of ischemic conditions of the limbs, gastrointestinal tract, and the heart (43–45). The most feared consequence of cerebral reperfusion injury is intracerebral hemorrhage (ICH) (46, 47).

EVT devices are well-suited to remove the target thrombus and anatomically clear the artery to restore blood flow, but do not offer direct therapy of metabolic consequences of ischema. For ameliorating metabolic disruptions, therapeutic hypothermia has been one of the most promising concepts based on its pleiotropic mechanisms of action (48, 49). In this perspective article we present the possible benefits of a novel form of therapeutic hypothermia: endovascular selective brain cooling, and how its adjunct application during endovascular stroke treatment could improve the outcome in LVO-AIS patients by reducing the deleterious impact of ischemia and reperfusion injury.