Medical management of acute cerebral ischemia in the elderly

Stroke ranks third as a cause of death in much of the industrial world, surpassed only by heart disease and cancer. Thrombotic and embolic arterial occlusions are the leading causes of cerebral infarction. Once a major cerebral infarction has occurred, therapy is limited to the prevention of complications and rehabilitation. Identification and treatment of stroke-prone patients are now not a standard part of medical practice. However, the proper management of the patient with acute cerebral ischemic or progressing stroke is a subject of debate. Treatment of progressing or acute cerebral ischemia is aimed at prevention of infarction in areas of the brain that are still viable. A number of therapeutic strategies are currently being investigated in the management of ischemic stroke.     

What animal models have taught us about the treatment of acute stroke and brain protection

Stroke research has progressed in leaps and bounds in the past decades. A driving force is the increasing availability of new research tools in this field (eg, animal stroke models). Animal stroke models have been extensively applied to advance our understanding of the mechanisms of ischemic brain injury and to develop novel therapeutic strategies for reducing brain damage after a stroke. Animal stroke models have been useful in characterizing the molecular cascades of injury processes. These “injury pathways” are also the targets of therapeutic interventions. The major achievements made in the past 2 decades applying animal stroke models include 1) the identification of the mediator role of excitotoxin and oxygen free radicals in ischemic brain injury; 2) the confirmation of apoptosis as a major mechanism of ischemic cell death; 3) the characterization of postischemic gene expression; 4) the delineation of postischemic inflammatory reaction; 5) the application of transgenic mice to confirm the roles of purported mediators in ischemic brain injury; 6) development of novel magnetic resonance imaging sequences for early noninvasive detection of ischemic brain lesions; and, 7) the development of novel therapeutic strategies based on preclinical findings derived from animal stroke models.     

Aldosterone: good guy or bad guy in cerebrovascular disease?

Stroke is a leading cause of disability in the Western world, yet the choices for therapeutic intervention are few. The complex role played by aldosterone in the pathogenesis of stroke is beginning to emerge. Chronic mineralocorticoid receptor (MR) blockade reduces the incidence of hemorrhagic strokes and the severity of damage caused by ischemic strokes. This appears to be a vascular phenomenon because MR blockade increases vessel lumen diameter, which presumably increases blood flow and perfusion of the tissue to reduce ischemic damage. However, the vascular protection afforded by MR antagonism is at odds with the results seen within the brain, where MR activation is required for neuronal survival. Both of these divergent effects have possible therapeutic implications for stroke.     

Challenges in Acute Ischemic Stroke Clinical Trials

There have been only 3 positive Phase III randomized clinical trials in acute ischemic stroke, all reperfusion therapies (NINDS; PROACT II; ECASS III). The only approved acute stroke therapy is <3-hour IV tPA. Although numerous compounds have shown benefit in animal models of brain infarction, there has never been a positive Phase III randomized clinical trial of a neuroprotectant in acute ischemic stroke. There are many challenges to acute stroke clinical trials but chief among these are the very short therapeutic window (??time is brain??) and the issue of stroke heterogeneity. Stroke is a syndrome and only a very small percentage of all stroke patients present to hospitals in time to consider reperfusion therapy. Many drugs have been rushed to trial prematurely based on inadequate preclinical testing. Many trials have been seriously underpowered due to overly optimistic treatment expectations and the risk of brain hemorrhage has precluded aggressive multimodal treatment strategies. Rather than simply relying on a clock, new imaging methods are being developed to identify patients with ??tissue at risk?? and ??salvageable brain?? regardless of time of stroke onset. The 7 STAIR conferences have been convened to address these and other challenges to acute ischemic stroke trial design and completion.     

急性缺血性脑血管病药物性脑保护的研究进展

兴奋毒性、钙超载、自由基反应、梗死周围除极、炎症和凋亡是造成缺血性脑损伤的中心环节.脑保护是治疗急性缺血性脑血管病的主要策略之一.处于临床研究阶段的脑保护剂有钙通道拮抗剂、兴奋性氨基酸受体拮抗剂、γ-氨基丁酸受体激动剂、抗氧化剂和自由基清除剂等等.     

Safety of intra-arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke

Stroke is the third cause of death and the leading cause of disability in adult subjects. Although stroke mortality has been declining in some countries, stroke morbidity has been increasing due to the aging of population and patients improved survival. Treatment with recombinant tissue plasminogen activator (rtPA) is successful provided it is administered within 3 hours of symptoms onset, but its use is limited to about 5% of the patients with acute ischemic stroke. Furthermore, no neuroprotective agent has yet been proven effective in human clinical trials. The development of other therapeutic strategies is, therefore, warranted. The use of stem cells in animal models has led to functional improvement following stroke. Recent publications have shown that bone marrow mononuclear cells (BM-MNC) therapy through intracoronary injection is a safe procedure in patients with acute or chronic ischemic heart disease. Based on these preliminary data, there has been growing interest in the study of BM-MNC transplantation for acute ischemic stroke. We report the first case of intra-arterial autologous BM-MNC transplantation for acute ischemic stroke.     

Treatment of acute ischemic stroke

Acute ischemic stroke is the third leading cause of death in the United States and the leading cause of adult disability. The direct and indirect costs of stroke care exceed $51 billion annually. In 1996, the US Food and Drug Administration approved the first treatment for acute ischemic stroke, intravenous tissue plasminogen activator. Later that year, the National Institute of Neurologic Disorders and Stroke (a branch of the National Institutes of Health) convened a consensus conference on the Rapid Identification and Treatment of Acute Ischemic Stroke, setting goals for stroke care in the United States. Since then, it has become imperative that emergency physicians understand the pathophysiology of stroke, the basis and rationale for treatment, and the therapeutic approaches. This article reviews the state of the art of acute stroke treatment, its foundation, as well as its future.     

Progesterone receptors: a key for neuroprotection in experimental stroke

Progesterone receptors (PR) are expressed throughout the brain. However, their functional significance remains understudied. Here we report a novel role of PR as crucial mediators of neuroprotection using a model of transient middle cerebral artery occlusion and PR knockout mice. Six hours after ischemia, we observed a rapid increase in progesterone and 5α-dihydroprogesterone, the endogenous PR ligands, a process that may be a part of the natural neuroprotective mechanisms. PR deficiency, and even haploinsufficiency, increases the susceptibility of the brain to stroke damage. Within a time window of 24 h, PR-dependent signaling of endogenous brain progesterone limits the extent of tissue damage and the impairment of motor functions. Longer-term improvement requires additional treatment with exogenous progesterone and is also PR dependent. The potent and selective PR agonist Nestorone is also effective. In contrast to progesterone, levels of the neurosteroid allopregnanolone, which modulates γ-aminobutyric acid type A receptors, did not increase after stroke, but its administration protected both wild-type and PR-deficient mice against ischemic damage. These results show that 1) PR are linked to signaling pathways that influence susceptibility to stroke, and 2) PR are direct key targets for both endogenous neuroprotection and for therapeutic strategies after stroke, and they suggest a novel indication for synthetic progestins already validated for contraception. Although allopregnanolone may not be an endogenous neuroprotective agent, its administration protects the brain against ischemic damage by signaling mechanisms not involving PR. Collectively, our data clarify the relative roles of PR and allopregnanolone in neuroprotection after stroke.     

Reperfusion strategies for acute ischemic stroke

Stroke remains a major cause of morbidity and mortality worldwide. Despite preventive measures, effective management strategies are needed to reduce the morbidity and mortality associated with this devastating condition. While the management of hemorrhagic stroke is mostly limited to supportive care, reperfusion strategies in ischemic stroke have been developed and continue to evolve. Conceptually, the pathophysiology of ischemic stroke is similar to that of acute myocardial infarction and the objective of management is similar (ie, to rapidly restore normal flow to reduce permanent damage). It is, therefore, not surprising that the management of acute ischemic stroke includes intravenous (IV) thrombolysis, the only Food and Drug Administration (FDA)-approved strategy at this point. In addition, there are a myriad of emerging endovascular interventional techniques. We review the current literature and discuss some of the technical aspects of endovascular therapy in the setting of acute ischemic stroke.     

Hyperacute Management of Ischemic Strokes: JACC Focus Seminar

Acute ischemic stroke is the leading cause of disability and among the leading causes of mortality worldwide. Intravenous tissue plasminogen activator has been a cornerstone for treatment of acute ischemic stroke for more than 20 years; however, its use is limited due to a narrow therapeutic window, several contraindications, and low efficacy to recanalize the artery in large vessel occlusion. Recently, the addition of endovascular mechanical thrombectomy of large artery occlusion has revolutionized the stroke treatment for most disabling strokes. The paper reviews updates to the thrombolytic treatment as well as catheter-based treatment, and results from recent trials in the selection of patients in an extended time window using perfusion imaging.     

The Management of Hypertension for an Acute Stroke: What Is the Blood Pressure Goal?

Stroke is the 4th leading cause of death in the US and a leading cause of disability among adults. Stroke is broadly classified into ischemic and hemorrhagic subtypes. Although the pathogenesis may differ between ischemic and hemorrhagic stroke subtypes, a unifying feature is that hypertension is a major risk factor for most ischemic and hemorrhagic strokes. Prevention of first and recurrent stroke is substantially dependent on blood pressure control. There is controversy about blood pressure management in acute stroke. In this review we discuss controversies about and guidelines for management of blood pressure in acute stroke. We subdivide our discussion to address important questions about acute blood pressure management in ischemic stroke, intraparenchymal hemorrhage, and subarachnoid hemorrhage. In addition, we address BP control recommendations when tissue plasminogen activator administration is being contemplated for treatment of acute ischemic stroke.     

Stroke Treatment Using Intravenous and Intra-Arterial Tissue Plasminogen Activator

OPINION STATEMENT: Acute ischemic stroke is the most common cause of adult disability in the world and the third most common cause of death. Early restoration of perfusion to ischemic brain has been a highly successful strategy to decrease the disability associated with acute ischemic stroke. For acute stroke, intravenous (IV) tissue plasminogen activator (t-PA) is the only proven acute treatment that results in improved clinical outcomes. IV t-PA is indicated for ischemic stroke when administered within 4.5?h or less of symptom onset. This 4.5-hour treatment window represents a significant expansion from the previous 3-hour treatment window for therapy. Despite a longer time window, patients have the greatest chance for an improved outcome when treatment occurs as soon as possible from the time of symptom onset. The Emergency Department goal for treatment is a door to t-PA administration time of 60?min. In order to facilitate rapid evaluation and treatment, systems of care that streamline treatment should be developed at every institution that cares for acute ischemic stroke patients. For those with contraindications to t-PA and those outside the treatment window, catheter-directed intra-arterial (IA) t-PA administration or mechanical clot extraction is a potential means of restoring brain perfusion. These therapies should not preclude the use of IV t-PA when feasible and are frequently only available at tertiary care centers. Technological advances in IA devices for mechanical clot extraction make this a promising and growing area for advancing stroke therapy but remain under ongoing investigation to establish improved clinical outcomes.     

体外反搏在缺血性脑血管病康复中的作用与机制

尽管治疗手段在发展,缺血性脑血管疾病仍是致死和致残的主要原因。体外反搏可增加脑血流灌注,可降低缺血区域的神经细胞损害。国内体外反搏治疗缺血性脑血管疾病的临床研究结果提示该方法有效、安全及不良反应轻微,但由于大多存在研究设计的缺陷,未能提供充足的临床证据。国外有限的研究提示了体外反搏对缺血性脑血管疾病具有良好的治疗效果。体外反搏对脑血管病的治疗机制尚未完全阐明,可能与增加脑部血流灌注,增加侧支循环形成,改善血管内皮功能及促进血管新生和脑重塑有关。体外反搏可能是一种很有潜力的缺血性脑血管疾病的治疗和辅助治疗手段,但期待更多前瞻性、随机对照临床试验的证实。     

Selective vulnerability of the brain: new insights into the pathophysiology of stroke

Stroke is a major cause of morbidity and mortality in the United States with 250,000 cases per year. Cerebral ischemia is the largest category of stroke with cardiac arrest, profound hypotension, and vascular occlusion the principal causes. Traditional approaches to the treatment of ischemic stroke focus on maintaining cardiac output, blood pressure, cerebral blood flow, and on preventing thrombosis. Recently, attention has been focused on developing new therapies that are directed toward abnormal biochemical events at excitatory synapses. Ischemia causes impairment of brain energy metabolism and the release of excessive amounts of glutamate into the extracellular space. This process secondarily excites neurons and further depletes energy stores. The excitotoxic hypothesis of brain injury proposes that glutamate is a principal cause of damage in ischemia. Three components of this hypothesis have been tested and largely proved in experimental studies in tissue culture and in animal models of stroke. First, elevated concentrations of glutamate cause excessive excitation at a subset of glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor. Second, excitation at this receptor leads to excessive influx of sodium chloride and water which causes acute neuronal damage, and calcium which causes delayed and more permanent damage. Third, pharmacologic blockade at the NMDA receptor-ion channel complex prevents ischemic neuronal damage. Studies using specific pharmacologic compounds that block glutamate's action hold particular promise for treating stroke in humans, including competitive antagonists at the NMDA glutamate binding site (for example, 2-amino-5-phosphonovalerate, AP5), noncompetitive antagonists at the calcium channel (for example, MK-801, dextromethorphan, ketamine), and agents that might be directed at the glycine, zinc, and magnesium sites.     

Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice

Cyclooxygenase-2 (COX-2), a prostanoid-synthesizing enzyme that contributes to the toxicity associated with inflammation, has recently emerged as a promising therapeutic target for several illnesses, ranging from osteoarthritis to Alzheimer's disease. Although COX-2 has also been linked to ischemic stroke, its role in the mechanisms of ischemic brain injury remains controversial. We demonstrate that COX-2-deficient mice have a significant reduction in the brain injury produced by occlusion of the middle cerebral artery. The protection can be attributed to attenuation of glutamate neurotoxicity, a critical factor in the initiation of ischemic brain injury, and to abrogation of the deleterious effects of postischemic inflammation, a process contributing to the secondary progression of the damage. Thus, COX-2 is involved in pathogenic events occurring in both the early and late stages of cerebral ischemia and may be a valuable therapeutic target for treatment of human stroke.     

调节性T淋巴细胞与缺血性卒中

卒中是一种高致死率和高致残率的脑血管病类型,其中缺血性卒中约占80％.目前认为,炎症机制在缺血性卒中的病理生理学进展中发挥重要作用.外周T淋巴细胞在脑缺血后24 h内浸润受损区域,参与脑组织炎症过程的进展.作为T淋巴细胞的一个亚群,调节性T细胞主要定位于缺血半暗带,但目前对其在缺血性脑损伤中的作用仍存在着争议.研究调节性T细胞在脑缺血中的作用机制,有助于进一步认识缺血性卒中的发病机制和发现新的治疗靶点.     

Hyperacute imaging of ischemic stroke: Role in therapeutic management

Ischemic stroke remains a significant cause of morbidity and mortality. Current therapeutic options for acute ischemic stroke include intravenous thrombolysis and endovascular approaches for recanalization of proximal arterial occlusion. The rapid identification of underlying stroke etiology or mechanism may facilitate selection criteria for emergent therapy. Hyperacute imaging plays an integral role in the delineation of stroke pathophysiology and the formulation of rational stroke therapy. Hyperacute imaging of ischemic stroke may demonstrate proximal vascular occlusion, compensatory collateral circulation, residual or collateral tissue perfusion, and the differentiation of ischemic core from penumbral regions. Characterization of the ischemic field, including core and penumbra, with various mismatch models on multimodal computed tomography or MRI may refine current therapeutic strategies for cerebral ischemia. The diagnostic and therapeutic role of hyperacute imaging has emerged as a pivotal component in the evaluation and management of ischemic stroke.     

伴心房颤动的急性缺血性卒中的治疗

心房颤动是缺血性卒中的一种重要病因.研究表明,与无心房颤动者相比,伴有心房颤动的卒中患者会出现更严重的神经功能缺损和更高的病死率.此外,心房颤动还是静脉溶栓后血管未能再通的独立危险因素,与转归不良相关.机械取栓治疗为伴有心房颤动的急性缺血性卒中患者提供了新的治疗方案.文章就合并心房颤动的急性缺血性卒中患者的静脉溶栓和机械取栓治疗进行了综述.     

Acute cerebral ischemia in a critical care unit. A review of diagnosis and management

With an increasing understanding of the pathophysiology of human brain ischemia, it appears that time is of critical essence in the diagnosis and management of the acute stroke victim. A review of the acute ischemic stroke patient in an intensive care setting is described. Recent knowledge of clinical stroke assessment is summarized, with further emphasis on in-hospital strokes. Acute stroke units are described with a focus on the general clinical approach to patients with acute cerebral ischemia: investigations, recent treatment advances, and rehabilitation. Unless patients with acute brain ischemia are given the opportunity for aggressive management, care, and enrollment into promising therapeutic protocols, ideally within an acute stroke unit setting, the tremendous burden of stroke will not be lifted.