Therapeutic hypothermia for stroke: Unique challenges at the bedside

 All this earlier research was inconclusive so why this repeat research rather than do some actual research that might get it successfully translated to clinical interventions?  I blame the mentors and senior researchers for the failure of setting correct objectives. The whole point of stroke research is to solve stroke, not just tell us of the problems that exist in solving stroke. LEADERS SOLVE PROBLEMS; Are you a leader or a mouse?

• hypothermia (54 posts to February 2011)

 

Therapeutic hypothermia for stroke: Unique challenges at the bedside

Je Sung You^1†, Jong Youl Kim^2† and Midori A. Yenari^3*

• ¹Department of Emergency Medicine, Yonsei University College of Medicine, Seoul, South Korea
• ²Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea
• ³Department of Neurology, The San Francisco Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA, United States

Therapeutic hypothermia has shown promise as a means to improving neurological outcomes at several neurological conditions. At the clinical level, it has been shown to improve outcomes in comatose survivors of cardiac arrest and in neonatal hypoxic ischemic encephalopathy, but has yet to be convincingly demonstrated in stroke. While numerous preclinical studies have shown benefit in stroke models, translating this to the clinical level has proven challenging. Major obstacles include cooling patients with typical stroke who are awake and breathing spontaneously but often have significant comorbidities. Solutions around these problems include selective brain cooling and cooling to lesser depths or avoiding hyperthermia. This review will cover the mechanisms of protection by therapeutic hypothermia, as well as recent progress made in selective brain cooling and the neuroprotective effects of only slightly lowering brain temperature. Therapeutic hypothermia for stroke has been shown to be feasible, but has yet to be definitively proven effective. There is clearly much work to be undertaken in this area.(But you did NOTHING TO SOLVE THAT PROBLEM!)

Introduction

Acute ischemic stroke is the primary cause of about 85% of strokes worldwide and is most frequently caused by blood clots or atherosclerosis occluding cerebral blood flow (1, 2). Studies have shown that decreasing the time between presentation and intervention can improve clinical outcomes (2, 3). Modern management efforts thus emphasize the time sensitivity of stroke treatment. Antiplatelet and anticoagulant drugs have long been the mainstay of ischemic stroke management, along with the use of acute thrombolysis and mechanical thrombectomy to revascularize thrombosed vessels (4–6). If initiated rapidly, these revascularization strategies reduce morbidity and improve neurological outcomes, although the window for these interventions is on the order of hours (6, 7). Unfortunately, due to a variety of constraints, a majority of patients tend to present too late for these interventions and are not eligible for potentially life-saving and disability-preventing treatments (8–11). Thus, adjunctive treatments may be needed to extend this critical time interval to offer treatments to a broader number of stroke victims.

Therapeutic hypothermia (TH) has been suggested as a potential approach to achieve the goal (12, 13). In 2002, two randomized controlled trials (RCT) showed the induction of mild hypothermia (32–34°C) produced more favorable neurologic outcomes and improved survival after cardiac arrest compared with patients for whom body temperatures were maintained in the normothermic range (14, 15). TH has since been rapidly implemented worldwide and established as a gold standard in the management of comatose survivors of cardiac arrest; however, TH has only been shown to be effective at the clinical level in patients suffering from cardiac arrest and in neonates suffering from hypoxic ischemic encephalopathy (HIE) (16–18). In this review, TH refers to cooling the body in order to preserve organ viability and is so far the most effective therapy for improving neurological outcomes in comatose survivors of cardiac arrest (14, 18, 19). Subsequent studies have also shown that modulation of body temperature to normal and slightly below normal levels may also be beneficial. Thus, the term targeted temperature management (TTM) refers to modulation of body temperature including TH.

In spite of the optimism of TTM in cardiac arrest and neonatal HIE, clinical applications of TTM in other acute brain injuries, such as hemorrhagic or ischemic stroke and traumatic brain injury, have yet to demonstrate improvement in clinical outcomes (20–25). Yet, multiple preclinical studies have consistently shown that TH induces multiple and synergistic effects for neuroprotection in experimental models (16, 26). A major challenge in translating this to the clinical level is that therapeutic hypothermia studies in many experimental models used small species where whole body cooling can be achieved in a short period of time. By contrast, humans have much larger mass, and whole body cooling to achieve target brain temperatures for optimal neuroprotection requires many hours. Furthermore, patients with stroke are typically older with comorbidities, which could complicate TH. Thus, selectively cooling the brain has the potential not only to achieve more rapid cooling but may reduce systemic complications. Efforts to achieve this included using internal catheters to reduce temperatures of the cerebral vessels, which would then cool brain tissue (23, 25), or cooling caps to directly cool the brain (27–29), but these approaches have achieved limited success. Regardless, it is clear that reducing brain temperature can improve neurological outcomes from many acute brain insults. This review covers the current state of TTM as it relates to clinical stroke care.

Mechanisms of hypothermic protection in experimental ischemic stroke

To understand the robust neuroprotective effects of TH, it is important to understand the preclinical works related to understanding why TH seems so effective. TH has long been thought to lead to beneficial effects by decreasing brain metabolism (16), but through multiple experimental studies, it has now been recognized that TH exerts neuroprotection by favorably altering a broad range of pathological pathways, including the regulation of brain metabolism, apoptosis, microglial activation, cerebral blood flow, inflammation, and neurotrophic factors (16, 26). As such, this may be a major reason why lowering brain temperature may lead to preservation of brain tissue and function.

Effect of hypothermia on brain metabolism, blood flow, and excitotoxicity

In ischemic stroke models, hypothermia to brain at temperatures of 33°C (mild hypothermia) showed improved cerebral blood flow and preservation of the cellular metabolic rate (30, 31). During stroke, cerebral blood flow (CBF) is disrupted following vessel occlusion. If blood flow is restored (reperfusion), there is a brief and abrupt overshoot of CBF, followed by gradual deterioration. Microvascular narrowing was thought to underlie this deterioration (32), and TH has been shown not only to improve and maintain CBF by preventing microcirculatory collapse but also seems to prevent this brief overshoot of CBF upon reperfusion (33).

Brain metabolism is also sensitive to temperature. Mild hypothermia reduces oxygen consumption by a ~5%/°C decrease in body temperature in the range of 22–37°C (2). Cerebral ischemia also leads to increased accumulation of extracellular glutamate and influx of calcium (34). Hypothermia has been documented to prevent glutamate accumulation and subsequent excitotoxicity mediated by calcium influx (26, 35). More recently, hypothermia also appears to suppress the calcium-sensing receptor (CaSR) expression, which regulates calcium influx and upregulates the inhibitory gamma-aminobutyric acid B receptor 1 (GABA-B-R1) (36). As such, hypothermia appears to induce neuroprotective effects in ischemia models by affecting multiple aspects of brain metabolism and neurotransmission.

Neuroprotection by hypothermia: Cell death pathways

Beyond early observations that hypothermia preserves tissue metabolic reserves and reduces ischemic elaboration of excitotoxins, hypothermia has also been shown to positively influence several ischemic cell death pathways, such as apoptosis (37). Several studies have shown that hypothermia can prevent apoptotic cell death in stroke models (38–40). TH was first shown to affect several aspects of the intrinsic pathway, ultimately leading to neuroprotection. The intrinsic pathway is initiated within the cell mitochondria via release of various factors, such as cytochrome c and apoptosis-initiating factor (AIF), into the cytosol (41). Mild hypothermia has been shown to increase the anti-apoptotic protein Bcl-2, which, in turn, inhibits cytosolic cytochrome c release and subsequent caspase activation (42). A few studies have also shown that mild hypothermia reduces the generation of pro-apoptotic Bax (43–46). Downstream of Bcl2, hypothermia has been shown to influence protein kinase C (PKC) family members, such as anti-apoptotic (PKCε) or pro-apoptotic (PKCδ), so as to lead to overreduction in apoptotic cell death (39).

The extrinsic apoptotic pathway is triggered via death receptors, which, when ligated, leads to cell death. A prototypical death receptor, Fas, and its corresponding ligand, Fas ligand (FasL), have also been studied in stroke models, and interrupting this pathway has been shown to improve outcomes in stroke models (47). TH has been shown to decrease the expression of Fas and FasL and subsequent activation of downstream caspase-8 (48–51).

TH can also affect caspase-independent apoptosis. The mitochondrial apoptosis-inducing factor (AIF) pathway involves direct apoptotic cell death and is capable of inducing apoptosis without activating caspases (52). Mild hypothermia suppressed AIF translocation from the mitochondria to the cytosol and led to reduced apoptotic cell death in an ischemic stroke model (53). In sum, TH is capable of influencing many cell death pathways in such a way so as to favor cell survival.

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