Myocardial Infarction Ebooks Catalog

Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

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Natural Secrets For Healing Your Heart

This eBook is devoted to exposing the secrets that cardiologists and surgeons don't want you to know, and how to take control of your own heart and heal yourself. Eight out of every ten coronary bypasses will not actually help the patient. So why risk being in the 80% that will get no benefit from a bypass? Learn to heal your own heart and keep yourself healthy with this eBook guide. Bob Livingston has poured years of research into his findings, and is now sharing the methods that he has developed from careful, methodical research that the medical industry would never allow. It would make them go bankrupt! You will learn what supernutrient doctors don't want you to know about, and how to make an all-natural, chemical and drug-free blood thinner And even more information that doctors don't want revealed to the public. You don't have to be one of the 70% of Americans diagnosed with heart disease. You can heal your heart!

Natural Secrets For Healing Your Heart Overview

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Alcohol and nonfatal myocardial infarction or incidence of CHD

Data on the incidence of myocardial infarction or CHD were available for about 40 of the cited cohorts. It is no longer disputed that drinkers as a group have a lower incidence of Table 1.1 Large population studies examining alcohol intake and cardiovascular disease 10 Puerto Rico Heart Health Program 11 Yugoslavia Cardiovascular Disease Study *Length of follow-up (years) +Number of incidence cases unless otherwise indicated CHD coronary heart disease CVD cardiovascular disease NHANES I the First National Health and Nutrition Examination Survey. *Length of follow-up (years) +Number of incidence cases unless otherwise indicated CHD coronary heart disease CVD cardiovascular disease NHANES I the First National Health and Nutrition Examination Survey. acute myocardial infarction or CHD than do non-drinkers. However, it is unresolved as to whether there is a dose-response relation between increasing alcohol intake and decreasing incidence and whether there is an increase in risk at the...

Establishing The Diagnosis Of Ischemic Stroke

Insular Ribbon Sign

Recent years have seen the emergence of successful treatment strategies for ischemic stroke, but these are most effective only when initiated within several hours after stroke onset. Therefore, extremely rapid diagnosis and initiation of treatment are critical in avoiding death or severe disability. Unfortunately, there are a variety of other clinical conditions that may mimic the presentation of acute ischemic stroke. These include intracranial hemorrhage, seizure, sepsis, cardiogenic syncope, complicated migraine, dementia, nonischemic spinal cord lesion, peripheral neuropathy, transient global amnesia, and brain tumor, among others. One recent study found that, of patients presenting to a hospital with stroke-like symptoms, the diagnosis of stroke or transient ischemic attack was never established confidently in 31 , and alternative diagnoses were ultimately made in 19 . Modern imaging techniques are capable of establishing the diagnosis with a high degree of certainty, and of...

Treatment of Heart Disease

Cardiovascular disease (CVD), which includes coronary heart disease, cerebrovascular disease (strokes), and peripheral artery disease, is the single most common cause of death in the United States. Caused by atherosclerosis, the buildup of fatty plaques along the inner walls of arteries, CVD causes significant disability and is a large source of health care costs. Behavioral medicine specialists have developed a number of interventions to prevent and treat CVD. The benefits from these interventions, although significant, are limited. Atherosclerosis has traditionally been viewed as a unidirectional process. Therefore, behavioral and medical interventions have been aimed at slowing, rather than reversing the sclerotic process. Recently, however, the Lifestyle Heart Trial attempted to reverse atherosclerosis through behavior change. This trial was notable for its comprehensiveness. Patients with severe heart disease were randomly assigned to either a standard-treatment control group or...

Lipids And Cardiovascular Disease

There are a substantial number of large epidemiological studies examining the relationship between dietary ATC intake and cardiovascular disease mortality (reviewed in 116-118 ). For example, studies carried out two decades ago showed a correlation between higher than expected mortality and very low dietary ATC intakes (as well as with very high ATC intakes 119 ). The basis of its cardioprotective effects is the ability of ATC to reduce damage caused by ROS in general, and specifically to inhibit the oxidation and MDA-modification of unsaturated lipids in low-density lipoprotein (LDL) particles 116,120,121 , These oxidized products ofLDL are highly damaging and initiate the formation of atherosclerotic plaques and lesions and are related to the course of myocardial infarction 116,122 . However, atherosclerotic plaque formation and the mechanisms for the ensuing increased morbidity and mortality are complex processes, which involve, for example, the production of superoxide by...

Myocardial infarction and depression

About one in six patients who have a myocardial infarction develop major depression. The occurrence of depression has been found to be independently associated with poor outcome, including poor quality of life, increased heart disease, and probably increased mortality. There is some evidence that those who have the severest heart disease are at greatest risk of an adverse outcome attributable to depression. It is in just these patients that depression is most likely to be missed because both doctor and patient understandably focus their attention on the heart disease and its treatment, rather than on psychological factors.

Coronary artery disease

Cardiovascular disease is substantially increased in diabetes, hyperglycaemia representing an independent risk factor. It is the chief cause of death and this observation strongly influences the management of diabetes by the important focus on reducing the risk factors responsible. Diabetes more than doubles the risk of cardiovascular disease. In the United Kingdom, 35 of deaths are attributable to cardiovascular causes, compared with about 60 in those with Type 2 diabetes, and 67 of Type 1 diabetic patients alive after 40 years of age. The relative risk is greater for women than for men, so that the sex ratio is equal in those with diabetes, with a loss of the usual male predominance. The development of MI over a period of seven years in middle-aged diabetic patients without known pre-existing coronary heart disease (CHD) is the same as that in non-diabetics with existing CHD. The presence of proteinuria and even microalbuminuria is associated with a particularly large risk of CHD...

Acute Myocardial Infarction

Acute myocardial infarction (AMI) should be mentioned as a heart disease in which notable changes of cardiac and plasma AM levels were observed (Kobayashi et al., 1996b Nagaya et al., 2000a). The plasma AM level was found to be elevated in patients with AMI, particularly in cases complicated by pulmonary congestion, and to return to the basal level within one to three weeks (Kobayashi et al., 1996b). The elevated plasma levels are correlated with pulmonary capillary wedge pressure, pulmonary arterial pressure, right atrial pressure and heart rate in the AMI patients (Kobayashi et al., 1996b). Thus, similar to the plasma AM levels in chronic heart failure, the increased concentrations in AMI may be partly related to depressed cardiac function. The follow-up study showed that in patients with AMI, as plasma AM levels increased, so too did mortalities (Nagaya et al., 1999). In addition to the plasma levels, it should be noted that both the peptide and mRNA expression of AM were markedly...

Ductdependent Congenital Heart Disease Emergency Treatment

Babies in the first few days of life who present with breathlessness and increasing cyanosis or a grey appearance largely unresponsive to oxygen supplementation are likely to have a duct-dependent congenital heart disease such as tricuspid or pulmonary atresia, critical aortic stenosis or hypoplastic left heart syndrome. An infusion of alprostadil at an initial dose of 0-05 micrograms kg min will maintain or increase the patent arteriosus ductus size temporarily until the patient can be transferred to a neonatal cardiology unit. Patients should be intubated and ventilated for transfer both because of the seriousness of their condition and also because the prostaglandin may cause apnoea. Full blood count, serum urea and electrolytes, calcium, glucose and arterial blood gases should be performed on all sick infants with congenital heart disease. A routine infection screen including blood cultures is also recommended. A full 12-lead electrocardiogram and chest radiograph are essential....

Valvular Heart Disease

The major complication one faces in dealing with patients with significant valvular heart disease is the potential for CHF. The indications for evaluation and treatment of valvular heart disease are identical to those in the nonpre-operative setting. Symptomatic stenotic lesions are associated with substantial risk of perioperative heart failure or shock and often require percutaneous valvulotomy or valve replacement prior to surgery (Reyes et al, 1994 Raymer and Yung, 1998 Torsher et al, 1998). In contrast, symptomatic regurgitant lesions are better tolerated periopera-tively and may be stabilized with intensive medical therapy and monitoring. An exception occurs when severe regurgitation exists with reduced ventricular function in which myocardial reserve is so limited that destabilization during perioperative stresses is likely. In such cases, consideration should be given to valve repair prior to nonemergent noncardiac surgery. Two other problems should be mentioned that are...

Cardiovascular Disease

The most common form of cardiovascular disease is called atherosclerosis, a disease of the arteries that can strike at any age, although it is not a serious threat until we reach our fifth or sixth decades. This is due in part to cellular changes that make the blood vessels less elastic (hardening of the arteries) and weaken the heart muscles, but it is largely due to poor diet and lack of exercise. This disease is characterized by a narrowing of the arteries, caused by the formation of plaques (deposits) containing dead cells and cholesterol. Several factors influence the appearance of plaques, including high levels of cholesterol (and cholesterol precursors, such as triglyceride) in the blood, high blood pressure, and cigarette smoke. The body removes excess cholesterol from the blood using a protein called apolipoprotein E (ApoE). ApoE, encoded by a gene on chromosome 19, binds to cholesterol and delivers it to liver cells, which store it for later use. Mutant ApoE loses the...

Inflammation And Cardiovascular Risk

Inflammation is an intrinsic part of the pathogenesis of atherosclerosis and cardiovascular disease (CVD)1. Accumulation of inflammatory cells in the vessel wall and predominantly in so-called vulnerable plaques suggests that the most vulnerable sites in the vessel wall have the most intense inflammatory activity2'3. Inflammatory cells whether in the vessel wall or the circulation produce a number of inflammatory proteins called cytokines which are central to the proinflammatory response of the vessel wall and the systemic acute phase response. Inflammatory cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6) stimulate the production of C-reactive protein (CRP) predominantly by the liver, but also by endothelial and smooth muscle cells in the vessel wall (Figure 6.1).

Cigarette Smoking And Cardiovascular Disease

Cigarette smoking-related cardiovascular diseases have been described widely. However, the mechanisms of their effects on cardiovascular system were not totally clear. The effects of nicotine and carbon monoxide on blood vessel walls, unfavorable lipid profiles, increased myocardial work and the decreased oxygen carrying capacity of the blood of smokers contribute to the overall effect of cigarette smoking on cardiovascular disease 3J. Of the increased cardiovascular risk caused by smoking, it is estimated that approximately one-tenth of this is due to smoking-induced changes in serum lipid 4 , The majority of studies indicate elevations in serum cholesterol, phospholipids, triglycerides, low-density lipoprotein (LDL) and increased hepatic lipase activity in smokers, with decreased serum high-density lipoprotein (HDL) cholesterol 5 , In addition, cigarette smoking is associated with unhealthy eating patterns, including increased intakes of alcohol, total fat, cholesterol, saturated...

Spontaneous Cardiovascular Disease in Animals

Cardiovascular disease occurs commonly in companion animals, particularly in domestic cats and dogs 1 . Myocardial disease represents a substantial portion of these disorders, many of which closely resemble cardiomyopathies in human patients 2 . Such disorders in cat, include hypertrophic 3,4 , dilated 5 , restrictive 6, 7 , and arrhythmogenic right ventricular cardiomyopathies (ARVC D) 8 . A heritable form of hy-pertrophic cardiomyopathy associated with a cardiac myosin binding protein C mutation has been recently reported in the Maine Coon cat breed 4 . In dogs, chronic myxomatous valve disease is the most prevalent cardiac disorder 9,10 , but cardiomyopathies occur frequently, particularly within certain medium and large-sized breeds 10 . Familial forms of dilated car-diomyopathy have been described in the Doberman Pinscher 11 , Irish wolfhound 12 , and Great Dane 13 , and a familial form of ARVC D has been reported in the boxer breed 14,15 . Dysplastic conditions of the right...

Cardiovascular disease hypertension lipids and myocardial infarction

Diabetic patients, particularly those with Type 2 diabetes and those with proteinuria, are at very considerable risk of excessive morbidity and mortality from cardiovascular, cerebrovascular and peripheral vascular disease leading to myocardial infarction (MI), strokes and amputations. Much effort must be given to reducing as far as possible the risk factors which are known to predispose to major atheromatous arterial disease. Many effective measures can now be taken, adding considerably to the complexity of treating diabetic patients, especially those with Type 2 diabetes. The difficulties and dangers of polypharmacy are discussed on page 14.

Clinical Trials of Aspirin in Acute Ischemic Stroke

Fewer recurrent ischemic strokes at 2 weeks among the aspirin-treated group (2.8 vs. 3.9 , 2p < 0.001), which was not offset by any significant excess of hemorrhagic strokes (0.9 vs. 0.8 ). The Chinese Acute Stroke Trial (CAST) compared 160 mg aspirin to placebo given for 4 weeks to 21,106 patients with acute ischemic stroke19 treated within 48 hours. Eighty-seven percent of patients had a brain computed tomography (CT) scan. The mortality rate after 1 month in the aspirin group was lower than in the placebo group (3.3 vs. 3.9 , 2p 0.04) with areduction in the rate of recurrent ischemic stroke at 1 month(1.6 vs.2.1 , p 0.01). A small (nonsignificant) increase in hemorrhagic stroke in the aspirin-treated group was observed (0.21 , p > 0.1). In the Multicenter Acute Stroke Trial Italy (MAST-I) study, 622 patients were randomized in a 2 x 2 factorial design to receive either a 1-hour infusion of 1.5 IU streptokinase or 300 mg aspirin or both, or neither.20 Streptokinase (alone or...

Trials of GP IIbIIIa Antagonists in Acute Ischemic Stroke

The abciximab in Acute Ischemic Stroke trial was a randomized, placebo-controlled dose-escalation study to examine the safety of abciximab in acute stroke.23 It randomized 74 patients within 24 hours of stroke onset to receive one of four doses of abciximab (by bolus with or without additional infusion, 54 patients) or placebo (20 patients). The median baseline National Institute of Health Stroke Scale (NIHSS) score was 15. The rates of asymptomatic ICH were 19 in the intervention group compared to 5 in the placebo group (p 0.07). Most (9 of 11) of the asymptomatic ICH patients had more severe stroke (NIHSS > 14). No cases of symptomatic ICH or major systemic bleeding occurred. There was a trend toward a lower rate of stroke recurrence (2 vs. 5 ) and a higher rate of functional recovery at 3 months in the group treated with abciximab than with placebo. The Safety of Tirofiban in Acute Ischemic Stroke (SaTIS) trial examined 250 patients 6-22 hours after stroke onset treated with...

Combination Anticoagulant and Antiplatelet Therapy in Acute Stroke

The Cochrane group examined (a) whether the addition of UFH or LMWH to anti-platelet agents offers any net advantage over antiplatelet monotherapy for acute stroke, and (b) the effectiveness of anticoagulants compared to antiplatelets in acute ischemic stroke.17 They included 4 trials of 16,558 patients, each of which specified aspirin (160-333 mg daily) as the control, and all of which randomized patients within 14 days of stroke onset. The anticoagulants tested were UFH and LMWH. Almost 98 of the patients were followed up for 6 months. This was largely influenced by the high-dose UFH group in 1ST (OR 1.38, 95 CI 1.05-1.82). An interaction by UFH dose (p 0.01) on recurrent stroke risk with combination UFH-aspirin therapy compared to aspirin monotherapy was observed, with a trend toward increased risk of recurrent stroke with high-dose UFH + aspirin (OR 1.22, 95 CI 0.92-1.62) and a trend toward reduced risk with low-dose UFH + aspirin (OR 0.75, 95 CI 0.56-1.03), equivalent to 10 fewer...

Current Barriers In Acute Stroke Care Pre Hospital Delays

Fewer than half of all patients with acute stroke are seen in the emergency department (ED) within 3 hours of symptom onset.4 Patients in remote locations or in hospitals without available stroke expertise may have even more limited access to thrombolysis. In a study of non-urban East Texas communities in the United States, only 1.4 of patients with ischemic stroke received IV rt-PA,5 versus 14.7 at a university hospital in Houston, the nearest major city.6 Other studies have linked racial, ethnic, geographic, or socioeconomic differences to low rates of rt-PA utili-zation,4,6 suggesting that populations most underserved by stroke expertise may have the lowest rates of rt-PA delivery.

Previous Stroke Neuroprotective Trials

Over the past 15 years, over 85 phase II and phase III drug trials have been conducted to investigate the clinical efficacy of stroke neuroprotective drugs that target one or more pathways of cell death.5 These drugs were developed based on the promising results of over a thousand experimental studies in animal stroke models.6 Unfortunately, no drug has survived the challenge of clinical testing. The most notable failure is the SAINT-II trial of NXY-059, a free radical scavenger. Rodent and primate studies had shown remarkable efficacy with this drug, and the initial SAINT-I trial in Australasia and Europe showed that NXY-059 improved functional outcome after acute stroke and reduced the risk of thrombolytic-associated hemorrhage.7 The field of stroke neuroprotection was optimistic that SAINT-II, the largest ever acute stroke trial, would yield positive results. However, like numerous other trials of nonthrombolytic drugs, SAINT-II proved to be a negative trial and the company...

Hypothermia for Ischemic Stroke

Early clinical data have shown promise for induced hypothermia for the treatment of acute ischemic stroke. Hypothermia acts by decreasing the cerebral metabolic rate, stabilizing cell membranes, preserving the integrity of the BBB, reducing the release of destructive enzymes, reducing the inflammatory response, and decreasing the release of excitotoxic neurotransmitters, such as glutamate and dopamine. Early treatment with hypothermia may reduce total infarct volume, and may prevent the development of cerebral edema. However, its use is associated with several potential adverse side effects, including an increased risk of infection, coagulopathy, hypokalemia, hyperglycemia, and cardiovascular suppression. Furthermore, when hypothermia is discontinued, a rebound elevation of ICP has also been noted, which may be fatal. The timing, degree, and duration of hypothermia in ischemic stroke have not been fully worked out, nor has the safest rate of re-warming. Numerous small studies have...

Antithrombotic Treatment of Acute Stroke Due to Large Artery Atherosclerosis

Early Recurrence Rates in Large Artery Disease Stroke due to LAA has been associated with a higher risk of early recurrence compared to cardioembolic, undetermined, and lacunar subtypes. A meta-analysis of population studies found a 4.5 recurrent stroke risk associated with LAA at 7 days and 9.4 recurrence at 1 month, a threefold increase in adjusted risk as compared to other subtypes.52 Patients with strokes caused by LAA appear to be at the greatest risk of worsening and recurrence in the early poststroke period. In the National Institute of Neurological Disorders and Stroke (NINDS) stroke database, patients with LAA had a 30 risk of worsening during acute hospitalization and a 7.9 risk of stroke recurrence within 30 days.

Cryothermia Induced Myocardial Infarction Model

A rat cryothermia-induced myocardial infarction model was used to study microvascularization and ventricular function after local alginate-encapsulated angiogenic growth factor treatment in rat model by Huwer et al. (21). After exposing the hearts of Sprague-Dawley rats through a left lateral thoracotomy, cryothermia was induced to the LV wall using a 5-mm cryoprobe cooled to -120 C, and 0.2 mL of calcium-algineate beads were injected into the cryoinjured tissue. The beads contained 0.4 g bFGF, 0.1 g vascular endothelial growth factor (VEGF), or 4.2 g epidermal growth factor (EGF). Four weeks later the chest was reopened and the formation of microvessels within the myocardial lesion, hemody-namics, and LV function were evaluated. The results of the study indicated that although the functional capillary density did not improve, there was a significant increase in the number of microvessels larger than capillaries. The increased number of microvessels within the infarcted tissue only...

Trials of Heparin in Acute Ischemic Stroke

Placebo-Controlled Trials of UFH, LMWH, and Heparinoids The International Stroke Trial (1ST)8 was a randomized, placebo-controlled trial of UFH (5000 or 12,500 IU twice daily) and aspirin (300 mg) in 19,435 unselected patients with acute stroke within 48 hours of symptom onset. Because of limited availability of neuroimaging, 33 of participants were enrolled with suspected but not proven ischemic stroke, some of whom may have suffered primary intracerebral hemorrhage (ICH).

Susceptibility To Ischemic Heart Disease

In a cohort study of ischemic heart disease among residents in the BFD-endemic area, a significant biological gradient was observed between the incidence of ischemic heart disease and the cumulative arsenic exposure (Chen et al., 1996). There was also an increased incidence of ischemic heart disease for patients affected with BFD as compared with the unaffected. The status of BFD may be considered an indicator of long-term arsenic exposure, systemic atherosclerosis and or susceptibility to arseniasis. The association between BFD and ischemic heart disease remained significant after adjustment for cumulative arsenic exposure and other risk factors, showing a multivariate-adjusted relative risk of 2.5. In a recent case-control study on ischemic heart disease in arseniasis-hyperendemic villages (Hsueh et al., 1998), serum samples of 74 patients and 193 matched healthy controls were tested for serum levels of micronutrients by HPLC. A significant reverse dose-response relationship with...

ABC of arterial and venous disease Acute stroke

Acute stroke is now a treatable condition that deserves urgent specialist attention. Drug treatment and specialist care both influence survival and recovery. This article considers the optimal approaches to diagnosis and early management. Stroke, a sudden neurological deficit of presumed vascular origin, is a clinical syndrome rather than a single disease. It is a common and devastating condition that causes death in one third of patients at six months and leaves another third permanently dependent on the help of others. Each year in the United Kingdom there are 110 000 first strokes and 30 000 recurrent strokes 10 000 strokes occur in people younger than 65 and 60 000 people die of stroke. It is the largest cause of disability, and more than five per cent of NHS and social services resources are consumed by stroke patients. Correct management relies on rapid diagnosis and treatment, thorough investigation, and rehabilitation. Patients should be assessed at hospital immediately after...

Pcos And Risk For Cardiovascular Disease

Evidence for Association Between Polycystic Ovary Syndrome, Cardiovascular Risk (CVR) Factors and Cardiovascular Disease (CVD) Recognized CVR factors Atherosclerosis coronary artery disease myocardial infarction athero Decreased sex hormone-binding globulin (SHBG), which is typical in PCOS and increases bioavailable testosterone, may be considered a surrogate marker of IR such that lower levels of SHBG are related to a greater degree of IR (18). Therefore, IR may in part indirectly contribute to CVR in PCOS by amplifying androgen excess. In addition to this possible selection bias, large-scale clinical trials evaluating the morbidity and mortality for CVD in women with PCOS are lacking. No long-term data of well-characterized women with PCOS are present in the literature, and the link of PCOS to primary cardiovascular events, such as stroke or myocardial infarction (MI), remains to be demonstrated. Epidemiological studies on isolated signs and stigmata of PCOS have produced mixed...

Cardiac Complications In Ischemic Stroke Patients

Acute stroke patients are at high risk for cardiac events, including myocardial infarction (MI) and dysrhythmias from autonomic derangement, particularly with strokes involving the insular cortex. Although the precise mechanisms and triggers for this have yet to be elucidated, it appears that there is a predominance of sympathetic activity associated with strokes involving the right hemisphere.115 Seizures that originate from the left temporal lobe may be more commonly associated with bradycardia and even cardiac asystole.116'117 In stroke patients, however, involvement of the right hemisphere appears to correlate most strongly with cardiac autonomic derangements. Colivicci et al.118 evaluated 103 patients with 24-hours Holter monitoring, and found a significantly higher rate of complex arrhythmias in patients with infarction of the right insular cortex. Meyer et al.119 assessed sympathetic function in acute stroke patients by measuring plasma epinephrine and norepine-phrine levels....

Trials Comparing Heparin to Aspirin in Acute Stroke

The Heparin in Acute Embolic Stroke Trial (HAEST) was a multicenter, randomized trial of the effect of LMWH (dalteparin 100 IU kg sc twice daily) or aspirin (160 mg once daily) for the acute treatment of 449 patients with ischemic stroke and atrial fibrillation (AF).13 The primary outcome was the rate of recurrent stroke within 14 days. No difference in rates of early recurrence (8.5 dalteparin treated vs. 7.5 aspirin treated) or good 3-month functional outcome was found. The frequency of early sICH was 2.7 on dalteparin versus 1.8 on aspirin. Tinzaparin in Acute Ischemic Stroke Trial (TAIST) was a randomized, doubleblind trial that compared high-dose tinzaparin (175 IU kg day), medium-dose tinza-parin (100 IU kg day), or aspirin (300mg day) started within 48 hours of acute ischemic stroke, given for up to 10 days.14 The proportion of patients independent at 6 months was similar in all the three groups (41.5 high-dose tinzaparin, 42.5 medium-dose tinzaparin, 42.5 aspirin). Rates of...

Implementation Of An Acute Stroke Team And Acute Stroke Protocols

The overwhelming prerogative, in thrombolysis for acute ischemic stroke, is the need for rapid, yet complete, evaluation of potential therapeutic candidates within the 3-hour treatment window. Time is the acute stroke clinician's worst enemy.33 The acute stroke protocol should begin at the first of point of contact with the healthcare system the call to an ambulance dispatcher. Stroke symptoms should be recognized and given high priority for dispatch. Emergency medical technicians (EMTs) should be trained to identify potential thrombolysis candidates in the field by recognizing signs of stroke,73,74 and several simple scales have been created for this purpose.75-78 Prenotification by the EMTs, before hospital arrival, allows time for notification of the acute stroke team and preparation of the CT scanner before patient arrival, and has been associated with fewer in-hospital delays in treatment.79,80 The initial evaluation, after arrival in the emergency department, should include a...

Alcohol Abuse And Cardiovascular Disease

Although there is considerable evidence that moderate drinking protects against mortality and morbidity from coronary heart disease 21,22 , heavy consumption is shown to have deleterious cardiovascular effects. It exerts its adverse effects by increasing the risks of cardiomyopathy, hypertension, and stroke 23 , Chronic ethanol consumption has been linked to the prevalence of hypertension, which contributes to an increased incidence of stroke. Heavy drinkers have alO mmHg higher systolic blood pressure than non-drinkers even though the relationship may differ between men and women 24 , Stroke is a leading cause of death and morbidity. Alcohol may increase the risk of stroke through various mechanisms that include hypertension, hypercoagulable states, cardiac arrhythmias, and cerebral blood flow reductions 25 , Hypertension, including borderline hypertension, is probably the most important stroke risk factor based on degree of risk and prevalence. Furthermore, cardiac morbidity,...

Monitoring Of Intracranial Pressure In Ischemic Stroke Patients

Able for stroke patients at risk for herniation, each with advantages and disadvantages. Unfortunately, noninvasive techniques have not proven to be sufficiently reliable for detecting elevations in ICP, and thus clinicians are left with a host of invasive techniques. EEG monitoring may be useful in acute stroke patients. Seizures are not uncommon following stroke, occurring in 6-9 of patients in the acute setting.112 The possibility of seizures in the patient with a massive stroke with cerebral edema is concerning, given that it could contribute to ICP elevations and worsen herniation effects. In one study of two groups of stroke patients, with (n 110) and without (n 275) seizures, the patients with seizures were significantly more likely to exhibit periodic lateralized epileptiform discharges (PLEDs) and frontal intermittent rhythmic delta activity (FIRDA).113 Some endorse the use of continuous EEG monitoring in patients with acute ischemic stroke, perhaps adding value to outcome...

Chronic Administration Of Am

There have been few reports which investigated the effect of chronic administration of AM in cardiovascular disease. Khan et al. (Khan et al., 1997a) reported that chronically infused human AM (200 ng h, for 2 weeks) had a hypotensive effect in both normotensive rats and spontaneously hypertensive rats without an increase in urinary volume or sodium excretion at a plasma AM concentration within the (3) Myocardial Infarction Nakamura et al. (Nakamura et al., 2002) examined the effects of long-term administration of AM on left ventricular remodeling following acute myocardial infarction. They infused human recombinant AM for 4 weeks in rats with myocardial infarction induced by left coronary artery ligation. Chronic infusion of AM reduced the heart weight body weight, left ventricular end-diastolic pressure, plasma endogenous rat AM levels, myocyte size, and collagen volume fraction of non-infarct LV area without affecting the infarct size, indicating that continuous administration of...

Polymorphisms Of Human Am Gene

Nucleotide sequencing of genomic DNA adjacent to the human AM gene revealed that there is a microsatellite marker with a variable number of cytosine adenine (CA)-repeats at 4 kb downstream from the 3'-end of the AM gene (Figure 1) (Ishimitsu et al., 2001a). We investigated the relation of this microsatellite DNA polymorphism flanking to the 3'-end of AM gene with genetic predispositions to develop various cardiovascular diseases. Genomic DNA was extracted from peripheral leukocytes of 300 normal healthy subjects (NH), 143 patients with essential hypertension (EH), 111 patients with coronary artery disease (CAD), 128 hemodialysis patients with type 2 diabetes mellitus (DM-HD) and 106 type 2 diabetic patients without nephropathy (DM) (Ishimitsu et al., 2001b, Ishimitsu et al., 2003). The microsatellite region containing CA repeats was amplified by PCR using fluorescence labeled primers. An aliquot of the PCR product was electrophoresed on a urea-polyacrylamide gel and the number of...

Thienopyridine Derivatives

Ticlopidine inhibits the P2Y12 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP IIb IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33 for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke.38,39 Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. The CAPRIE trial found that compared to aspirin (325 mg daily), clopidogrel (75 mg daily) was associated with RRR of 8.7 (p 0.043) for the composite endpoint of ischemic stroke, MI, or vascular death among 19,185 subjects with stroke, MI, or peripheral arterial...

Telemedicine As A Unique Intervention

Center, including acute stroke teams, stroke units, written care protocols, an integrated emergency response system, around-the-clock availability, and interpretation of computed tomography (CT) and rapid laboratory testing.3,12 However, a recent U.S. survey revealed that less than 10 of hospitals met the BAC criteria for a primary stroke center, although 75 of responding neurologists, neurosurgeons, and emergency physicians believed that their own hospital did meet guidelines. This disconnect is not trivial a community hospital in suburban Maryland is among many to have implemented guidelines, increasing the proportion of patients safely treated with IV rt-PA.13 Implementation of BAC guidelines in New York State improved the frequency of rt-PA delivery, decreased protocol violations, and shortened pretreatment latency.14 If a community hospital cannot provide the radiological and clinical stroke expertise to meet these guidelines, participation in a TeleStroke network may help a...

Initial Stabilization

In stroke patients presenting to the ED, the first goal of treatment is immediate cardiac and respiratory stabilization. The systemic blood pressure is most often elevated in the setting of an acute stroke as the result of a catecholamine surge, and if the patient is hypotensive, the clinician should consider a concomitant cardiac process, such as myocardial infarction (MI), congestive heart failure (CHF), or pulmonary embolism (PE). Stroke patients commonly have airway compromise, either secondary to a depressed level of consciousness or due to mechanical dysfunction of the airway from the stroke itself. Either mechanism can increase the risk for aspiration in the acute setting. Furthermore, patients with large hemispheric strokes or lesions involving the brainstem may be particularly prone to emesis, another predisposing factor for aspiration. The emergency physician must weigh the risks of the patient aspirating in this setting versus the loss of aspects of the neurological exam...

Antithrombotic Therapy for Acute Cardioembolic Stroke

Acute Anticoagulation for AF-associated Stroke HAEST and IST provided valuable data on relatively large numbers (449 in HAEST, 3169 in IST) of patients with AF-associated ischemic stroke treated with acute anticoagulation (danaparoid in HAEST, UFH in IST). HAEST found no reduction in early stroke recurrence or effect on late functional outcome in the LMWH arm. In contrast, IST found a dose-dependent reduction in early recurrence rates, but no late functional benefit associated with UFH. However, this was offset by an increase in rates of sICH among patients with AF receiving UFH, with no net benefit in the composite outcome of recurrence stroke and sICH combined. The reasons for the discrepancy between trials is unclear. It is generally believed that the rates of embolization from left ventricular thrombus occurring with acute myocardial infarction, left ventricular aneurysm formation, and idiopathic dilated cardiomyopathy are higher than those from the left atrial appendage...

Neuroimaging Stroke Subtype and Outcome

Radiological assessment of ischemic stroke provides an indication of outcome, as the imaging defines the extent and location of permanent brain injury and provides clues as to the stroke subtype. The current recommendation for imaging the patient with an acute stroke-like deficit is a noncontrast computed tomography (CT) scan to be performed within 30 minutes of arrival at an emergency ward.20 However, standard CT and magnetic resonance imaging (MRI) brain imaging techniques show infarcted regions hours to days after symptom onset. In contrast, recent work has demonstrated that advanced MRI techniques can predict final stroke size in the acute setting.21 The power of diffusion- and perfusion-weighted MRI techniques in detecting early ischemic injury has raised the question of whether acute diffusion perfusion MRI should replace CT as the standard imaging technique for emergency stroke evaluation (Table 9.2).22-26 Using clinical and emergency CT findings, the TOAST investigators found...

Performance of a Validated Examination

Shafqat et al.20 previously validated the National Institutes of Health Stroke Scale (NIHSS) assessment as a reliable method of evaluating patients with stroke symptoms at a bandwidth of 384 kbit s comparing a bedside neurologist to a telemedicine-enabled neurologist teamed with a bedside nurse in patients with ischemic stroke and NIHSS scores ranging from 1 to 24. There was an excellent correlation between bedside and remote scores (inter-rater correlation coefficient 0.97, p < 0.001) with only minimal increases in the time to perform the evaluation. The inter-rater agreement between telemedicine and bedside examinations was similar to that between any two bedside examinations in previous validation studies of the NIHSS.21 The remote evaluation of acute ischemic stroke (REACH) project validated the NIHSS in clinical practice with an excellent correlation between bedside and remote NIHSS scores (r 0.96,p 0.0001).22 Observational data among stroke patients from Handschu et al.23...

Accurate Evaluation of Transmitted Radiology Images

The rapid transmission and accurate interpretation of radiological images are essential in determining eligibility for IV thrombolysis among patients with stroke symptoms. Because the accuracy of interpreting these radiological studies affects outcomes after thrombolytic therapy, the person interpreting these images must be able to detect exclusion criteria for the administration of IV rt-PA. Intracranial hemorrhage on initial CT is an absolute contraindication, and the European Cooperative Acute Stroke Study (ECASS) trial and other data suggest that hypodensity on acute brain CT is associated with hemorrhagic transformation after thrombolysis, especially when such a hypodensity occupies greater than one third of the middle cerebral artery territory (> 1 3 MCA).24,25 The contribution to hemorrhagic transformation after thrombolysis of early ischemic changes (EIC), such as edema, lesser hypodensity, sulcal effacement, or ventricular compression, is more controversial. CT protocol...

Implications for Subacute Management Based on Etiology

Cardioembolism Cardioembolism accounts for approximately 30 of all stroke and 25-30 of strokes in the young (age < 45 years).42 1 AF accounts for a large proportion of these strokes (15-25 ). Symptoms may be suggestive, but they are not diagnostic. Repetitive, stereotyped, transient ischemic attacks (TIAs) are unusual in embolic stroke. The classic presentation for cardioembolism is the sudden onset of maximal symptoms. The size of the embolic material determines, in part, the course of the embolic material. Small emboli can cause retinal ischemic or lacunar symptoms. Posterior cerebral artery territory infarcts, in particular, are often due to cardiac embolism. This predilection is not completely consistent across the various cardiac structural abnormalities that predispose to stroke, and may be due to patterns of blood flow associated with specific cardiac pathologies. An ischemic stroke is considered cardioembolic if the clinical and neuroimaging findings support this diagnosis...

Combined Intravenous and Intra Arterial Thrombolysis

Some studies have evaluated the feasibility, safety, and efficacy of combined IV rt-PA at a dose of 0.6 mg kg with IAT in patients presenting with acute strokes within 3 hours of symptom onset.31-34 This approach has the potential of combining the advantages of IV rt-PA (fast and easy to use) with the advantages of IAT (directed therapy, titrated dosing, mechanical aids to recanalization, and higher rates of recanalization), thus improving the speed and frequency of recanalization. The IMS II objective was to continue investigating the feasibility of the combined IV and IA approach to restore cerebral blood flow in acute stroke patients.37 The difference between IMS I and IMS II is that IMS II used the EKOS microcath-eter to deliver the rt-PA into the clot, using microcatheter ultrasound technology. The rationale is that the ultrasound energy delivered in the clot loosens the fibrin strands, increasing the permeability and penetration of the thrombolytic agents. In IMS II, patients...

Pharmaceutical Drug Trials Antioxidants Free Radical Scavengers

A trial of Ebselen PZ51, a selenoorganic compound with glutathione peroxidase-like action, is currently in phase III of clinical trial. A small, randomized, double-blind, placebo-controlled trial of Ebselen initiated within 48 hours after stroke suggested protective efficacy as measured by the Glascow Outcome Scale (GOS) and Barthel Index (BI) at 1 month (p 0.023), but not at 3 months (p 0.056). Better clinical outcomes were observed if Ebselen administration was initiated less than 24 hours after symptom onset, but not greater than 24 hours.19 The Edaravone Acute Infarction Study (EAIS), a double-blind, randomized, placebo-controlled study looking at the effect of Edaravone (MCI-186) administered within 72 hours after ischemic stroke onset, yielded promising results (modified Rankin Scale mRS score significantly improved p 0.0382).20 The agent has been clinically available in Japan since 2001 however, it has not been followed up with either further study or clinical usage in the...

Periinfarct Depolarizations

Brain tissue depolarizations after ischemic stroke are believed to play a vital role in recruiting adjacent penumbral regions of reversible injury into the core area of infarction. Cortical spreading depression (CSD) is a self-propagating wave of electrochemical activity that advances through neural tissues at a rate of 2-5 mm min, causing prolonged (1-5 min) cellular depolarization, depressed neuro-electrical activity, potassium and glutamate release into adjacent tissue and reversible loss of membrane ionic gradients. CSD is associated with a change in the levels of numerous factors including immediate early genes, growth factors, and inflammatory mediators such as inter-leukin-1b and TNF-a 70 . CSD is a reversible phe-nomenon,and,while implicated in conditions such as migraine, reportedly does not cause permanent tissue injury in humans. In severely ischemic regions, energy failure is so profound that ionic disturbances and simultaneous depolarizations become permanent, a process...

The Neurovascular Unit

Although many proteases including cathepsins and heparanases contribute to extracellular matrix proteolysis, in the context of stroke, plasminogen activator (PA) and MMP are probably the two most important. This is because tissue plasminogen activator (t-PA) has been used successfully as a stroke therapy, and because emerging data show important linkages between t-PA, MMPs, edema, and hemorrhage after stroke. The MMPs are zinc endopeptidases produced by all cell types of the neurovascular unit 89 , that are secreted as zymogens requiring cleavage for enzymatic activation. MMPs can be classified into gelati-nases (MMP-2 and -9),collagenases (MMP-1,-8,-13), stromelysins (MMP-3, -10, -11), membrane-type MMPs (MMP-14, -15, -16, -17), and others (e.g., MMP-7 and -12) 90 . Together with the PA system, MMPs play a central role in brain development and plasticity as they modulate extracellular matrix to allow neurite outgrowth and cell migration 91 . Upstream...

And Longterm Neuroprotection

While the above discussion concerned neuroprotection in the hyperacute and acute stages after stroke, there is a rationale for using neuroprotective agents before stroke, in high-risk populations such as patients undergoing carotid endarterectomy, carotid angioplasty or stent placement, coronary artery bypass grafting, cardiac valvular surgery, repair of aortic dissections, and heart transplant. Similarly, drugs such as aspirin, clopidogrel (Plavix ), aggrenox, and warfarin, which reduce the actual risk for stroke, can be considered long-term neuroprotective agents. Newer agents that target the vascular endothelium and cerebral microcirculation - notably thiazide diuretics, angiotensin-converting enzyme inhibitors and hydroxy- 3-methylglutaryl- Co A (HMG-CoA) reductase inhibitors (statins) - have been shown to reduce the risk for stroke as well as improve outcomes after stroke 245-248 . Statins act by enhancing the endothelial release of nitric oxide, which relaxes vascular smooth...

Physiological Strategies Hypothermia

As with all molecular and biochemical pathways, the major mechanisms of cell death are temperature-dependent. Hypothermia can protect against multiple deleterious processes, including oxidative stress, inflammation, lipid peroxidation, and activation of cysteine or serine proteases.88-94 Each degree of temperature decline reduces the rate of cellular respiration, oxygen demand, carbon dioxide production by 10 .95 Preclinical and clinical results have been encouraging, making hypothermia an attractive physiological therapy that targets multiple injury mechanisms. However, the therapeutic time window for hypothermia is narrow.96 In one study, hypothermia proved beneficial if initiated 30 minutes before stroke onset, but not 10 minutes after stroke onset.97 Based on these results, additional controlled trials are now underway to test the therapeutic impact of hypothermia combined with thrombolysis. The results of a recent trial (Cooling for Acute Ischemic Brain Damage COOL-AID )105...

Trials of Unfractionated Heparin Compared to LMWH and Heparinoids

Relatively few data exist concerning the relative benefits of UFH, LMWH, and heparinoids in acute stroke treatment. In 2005, the Cochrane Collaboration reviewed trials comparing LMWHs or heparinoids with UFH in acute ischemic The PROTECT trial looked at certoparin, a LMWH, and compared it to UFH for the prevention of thromboembolic complications in patients with acute ischemic stroke.16 It was a double-blinded trial of 545 patients randomized within 24 hours of stroke onset. Certoparin 3000 U anti-Xa once daily was compared to UFH 5000IU sc three times daily, both given for 12-16 days. The rates of major thromboembolic events were 6.6 in the certoparin group compared with 8.8 in the UFH group, indicating noninferiority of certoparin (p 0.008). There was no difference in major bleeding rates between groups (1.1 in certoparin vs. 1.8 in UFH group). It was concluded that certoparin was at least as effective and safe as UFH for the prevention of thromboembolic complications in this trial.

Subacute Care and Management

In addition to access to acute stroke care, referral to stroke centers may also be important for the comprehensive quality of care in all patients presenting to the hospital with stroke.45 A study of patterns of care among patients with suspected stroke presenting to the EDs in rural East Texas hospitals revealed that head CT was performed in only 88 and ECG was performed in only 85 of patients blood pressure lowering was inappropriately aggressive, yielding pressures below current recommendations.5 Other studies have shown that telephone consultation for cognitive testing may provide a useful method for the diagnosis of poststroke dementia.46 Even after discharge, telemedicine-enabled family discussions may be helpful for caregivers of stroke survivors.47 In addition, telemedicine is useful for stroke rehabilitation in the subacute or postdischarge setting.48

Financial And Legal Considerations Opportunities for Community and Rural Hospitals

Financial and legal challenges will help shape the scalability and widespread clinical utility of telemedicine for acute stroke. Smaller hospitals often face a limited supply of local stroke specialists, the recruitment of which is often shaped by available salaries, emergency coverage requirements, opportunities for vacation time, and the richness of academic interaction. Telemedicine can collapse the problems associated with obtaining specialist care in neurologically underserved rural and urban communities. The cost of a telemedicine service to provide 24-7 acute stroke coverage is financially advantageous compared to retaining a full time on-site stroke expert, may support local stroke center designation at the spoke hospital, and prevent re-routing of patients away from the hospital as disease-specific triage algorithms emerge related to stroke. Smaller hospitals can therefore increase operational efficiency, particularly when the need for a specialist is infrequent or when...

Nonpharmaceutical Approaches Albumin

Ginsberg's pioneering animal research has shown that albumin infusions enhance red cell perfusion and suppress thrombosis and leukocyte adhesion in the microcirculation, particularly during the early reperfusion phase.54 Albumin also improves microcirculatory flow, plasma viscosity, red cell deformability, and oxygen transport capacity. In addition, albumin has potent antioxidant and antiapoptotic effects. In experimental stroke, albumin has been shown to reduce infarct size, improve neurofunction scores, and reduce brain edema.55 In the Albumin in Acute Stroke (ALIAS) phase II trial, an open-labeled, dose-escalation, nonrandomized pilot clinical trial conducted at two centers in North America, albumin was found to be safe and effective in reducing stroke-related brain injury.56,57 Eighty-two subjects with an NIHSS> 6 received 25 albumin within 16hours of stroke onset in two doses, 0.34-1.03 and 1.37-2.05 g kg. Nearly half of the patients (42) also received rt-PA. The probability of...

Reimbursement Licensure and Malpractice Barriers

Stroke consultants may be deterred from providing telemedicine-based consultation by the requirement of securing licensure in all states in which they provide consultation. However, acute stroke consultation may be exempt from these rules in states that make exceptions for emergency situations, limited duration of clinical care, or consultation to patients in bordering states. Still, other states prohibit ongoing

Anterior Circulation Thrombolysis

Internal Carotid Artery Occlusion Acute stroke due to a distal ICA T (T terminus) occlusion carry a much worse prognosis than MCA occlusions. In a recent analysis of 24 consecutive patients (median NIHSS 19) presenting with T occlusions of the ICA who were treated by IAT using urokinase at an average of 237 minutes from symptom onset, only four patients (16.6 ) had a favorable outcome at 3 months. Partial recanalization of the intracranial ICA was achieved in 15 (63 ), of the MCA in 4 (17 ), and of the ACA in 8 patients (33 ). Complete reca-nalization did not occur. The presence of good leptomeningeal collaterals and age < 60 years were the only predictors of a favorable clinical outcome.26 New treatment strategies, such as the combination of IV rt-PA and IAT27, or the use of new mechanical devices13 may improve the outcome in these patients.

Intravenous Thrombolytics

Thrombolytic agents cause the breakdown or dissolution of thrombi. Many of these agents work by converting inactive plasminogen into plasmin, a serine protease, which then cleaves fibrin within the thrombus (Fig. 3.1). Agents that have been studied in acute ischemic stroke include human rt-PA, urokinase, streptokinase, and desmoteplase. Systemic administration of these agents may also cause systemic fibrinogen degradation, reduction in circulating plasminogen and a2-antiplasmin, inactivation of factors V and VIII, platelet disaggregation, and possibly platelet This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This...

Rationale For Therapy

Cerebral infarction may result from large artery atherosclerosis, cardiac embolism, small artery lipohyalinosis, cryptogenic embolism, or, more rarely, from other diverse conditions such as arterial dissection, infective endocarditis, and sickle cell disease.2 Arterial occlusion is the cause of at least 80 of acute cerebral infarctions.3,4 Acute Ischemic Stroke An Evidence-based Approach, Edited by David M. Greer. Copyright 2007 John Wiley & Sons, Inc.

Acute Antithrombotic Treatment Of Stroke Subtypes

Although several approaches to stroke classification have been described, the most common mechanism-based classification in current use is the system described by the TOAST investigators.45 This classification describes five major subtypes of ischemic stroke based on the results of neuroimaging and other medical investigations, namely (1) LAA, (2) cardioembolism, (3) small-vessel occlusion, (4) stroke of other determined etiology, and (5) stroke of undetermined etiology. Inter-rater reliability of the TOAST scheme has been reported as moderate-to-substantial (K 0.5-0.7).

Limited Access to Stroke Expertise

Even when rt-PA is delivered to patients with ischemic stroke, higher rates of adverse outcomes occur when thrombolytic therapy is delivered without consulting physicians with specialized stroke expertise. In one community-based experience, 16 of treated patients developed symptomatic ICH compared to 6 of patients randomized to receive rt-PA in the NINDS trial. Although 96 of treatment decisions involved a neurologist, deviations from the NINDS guidelines were observed in 50 of treated patients.7 Aggressive corrective measures increased the rate of rt-PA administration while reducing symptomatic ICH to 6 among treated patients at the same hospitals.8 Other studies have similarly linked increased rates of protocol violations to increased rates of symptomatic ICH or mortality.9,10

Clinical Outcomes Following Tele Stroke Intervention

In the TEMPiS TeleStroke system, the probability of a poor outcome (Barthel Index Score < 60 or modified Rankin Scale Score > 3) was lower in patients networked to telemedicine-enabled consultation.41 Three thousand one hundred and twenty-two patients with ischemic stroke were examined in a nonrandomized, open-intervention study between two supporting academic hospitals and 10 community hospitals (five non-networked hospitals matched to five networked hospitals). Telemedicine intervention was associated in a multivariate analysis with a reduced probability of poor outcome (death, nursing home placement, or severe disability) after 3 months (OR 0.62, 95 CI 0.52-0.74, p < 0.0001). Death or institutionalization alone was not significantly reduced in patients receiving telemedicine intervention (OR 0.88, 95 CI 0.71-1.06 p 0.18). The impact was primarily of reduced probability of severe disability (14 receiving telemedicine intervention vs. 21 of control patients returned home with...

Identifying The Vascular Lesion

Cta Absent Right Pcom

Ischemic stroke occurs because of impairments in microvascular perfusion of affected brain tissue. However, the vascular event that results in impaired perfusion often occurs in a macroscopically visible vessel. Imaging studies that can study these vessels provide several kinds of important information to the stroke neurologist. First, by definitively demonstrating a vascular lesion that could be responsible for ischemic symptoms, vascular imaging can help to cement the diagnosis of an acute ischemic stroke, especially when DWI is not available and other studies are equivocal or negative. Second, the location of the vascular lesion conveys important prognostic information. In general, vascular lesions that involve larger, more proximal arteries that serve larger volumes of tissues cause infarcts that result in more severe neurologic deficits and a greater likelihood of hemorrhagic transformation. Finally, vascular imaging can be essential in guiding therapy. Intra-arterial...

Extracranialintracranial Arterial Bypass

The potential benefit of EC-IC bypass, therefore, has not been well studied in acute stroke patients carefully selected using newer physiological methods, including PET, xenon CT, single-photon emission computed tomography (SPECT), or CT or MR perfusion.5 Ongoing trials such as the Carotid Occlusion Surgery Study (COSS), the entry criteria of which include recent symptomatic occlusion of the ICA and increased OEF measured by PET, may help to clarify the benefit of emergency EC-IC bypass for selected patients (Figure 6.2). The Japanese EC-IC Bypass Trial (JET) is another ongoing randomized trial of EC-IC bypass in patients with severe hemodynamic failure measured by SPECT. Although final results are pending, JET preliminarily demonstrates a reduced incidence of major stroke or death in the 2-year period after surgery.28,29 With respect to timing of surgery, there is little evidence to either support or challenge the use of emergent EC-IC bypass in the setting of acute cerebral...

Endovascular Thrombectomy

Phenox Clot Retriever

The Concentric Retriever (Concentric Medical Inc., Mountain View, CA), a flexible, nitinol wire with helical tapering coil loops (X5 and X6) that is used in conjunction with a balloon guide catheter (8 or 9 French) and a microcatheter, is the only device currently approved by the FDA for the endovascular treatment of stroke patients (Fig. 4.3).13 The second-generation devices (L5 and L6) differ from the X devices by the inclusion of a system of arcading filaments attached to a nontapering

The MERCI and MultiMERCI Trials

The MERCI trial was a prospective single-arm, multicenter trial designed to test the safety and efficacy of the MERCI clot retrieval device to restore the patency of intracranial arteries in the first 8 hours of an acute stroke. All patients were ineligible for IV rt-PA. The occlusion sites were the intracranial vertebral artery, basilar The Multi-MERCI trial was an international multicenter, single-arm trial with three objectives to gain greater experience with the first-generation MERCI retrieval device (X5 and X6) in patients ineligible for IV rt-PA to explore the safety and technical efficacy of the MERCI retriever in patients treated with IV rt-PA who failed to recanalize and to collect safety and technical efficacy data on a second-generation MERCI retrieval device (L5). The primary outcome was vascular reca-nalization and safety. One hundred and eleven patients received the thrombectomy procedure. Mean age was 66.2 17.0 years, and baseline NIHSS score was 19 6.3. Thirty...

Efficiency of Thrombolytic Administration

In the first 27 months of our own TeleStroke experience,30 26 consultations were requested 12 began within 3 hours of symptom onset. Eight of these 12 patients had acute ischemic stroke, of which 2 were not treated due to mild deficits. Three were diagnosed with TIA or migraine, and one with a subdural hematoma not detected at the local facility. For the 12 acute cases for whom rapid diagnosis and management was essential, we determined the mean times from symptom onset to start of TeleStroke consultation and from consultation start to drug delivery or to determination of rt-PA ineligibility (shown in Fig. 10.4). The REACH system in southern Georgia (United States) and the TEMPiS system in Germany reported decreased latency to rt-PA delivery on a larger scale. REACH system investigators reported 194 acute stroke consultations delivered via telemedicine. The time from symptom onset to rt-PA delivery decreased from 143 minutes in the first 10 patients treated to 111 minutes in last 20...

Stroke Subtype Predicts Outcome

Patients with large vessel atherothrombotic stroke have been reported to have worse short- and long-term survival as compared to other subtypes of stroke.5-11 In a population-based study from Rochester Minnesota, only 24 of patients classified as atherothrombotic were independent during the period of worst deficit and 50 were independent at 1 year.9 Large vessel atherothrombotic stroke patients also have the highest rate of recurrent stroke.6,10,11 Cardioembolic strokes may also have poor outcome, especially with large emboli as in AF.12,13 In the Rochester population, patients with cardioembolic stroke were the most impaired during the hospitalization only 14 were independent as compared to 38 with lacunar stroke, 24 with atherosclerotic stroke, and 27 with ischemic stroke of unknown cause.14 The latter group probably included patients with emboli of unknown origin. As evidence of the proportion of patients with devastating strokes, patients classified as cardioembolic subtype were...

Mechanisms of Ischemic Cell Death

Mechanisms Ischemic Cell Injury

Ischemic stroke compromises blood flow and energy supply to the brain, which triggers at least five fundamental mechanisms that lead to cell death excito-toxicity and ionic imbalance, oxidative nitrative stress, inflammation, apoptosis, and peri-infarct depolarization (Fig. 1.1). These pathophysiological processes evolve in a series of complex spatial and temporal events spread out over hours or even days

Blood Pressure Management

Manipulation of blood pressure becomes necessary in many ischemic stroke patients, as patients with ongoing ischemia and fixed stenotic arterial lesion(s) may require blood pressure management to feed the ischemic penumbra. Conversely, patients with cerebral edema may require blood pressure lowering to reduce the detrimental effect of increased cerebral blood flow (CBF). In the normal human brain, CBF is kept relatively constant by the mechanism of cerebral autoregulation. This applies throughout a range of CPP from approximately 40 to 140 mm Hg. Beyond this range, the autoregulatory capacity is overwhelmed, and at pressures below 40 mm Hg further ischemia ensues. At pressures above 140 mm Hg, cerebral edema often worsens. Both of these circumstances assume an intact autoregulatory capacity, which may be significantly impaired in acute stroke patients. Older patients, or patients with chronic hypertension, often have poor vasoreactivity of the cerebral resistance vessels, perhaps...

Excitotoxicity and Ionic Imbalance

Ischemic stroke results in impaired cellular energy metabolism and failure of energy-dependent processes such as the sodium-potassium ATPase. Loss of energy stores results in ionic imbalance, neurotrans-mitter release, and inhibition of the reuptake of excitatory neurotransmitters such as glutamate. Glutamate binding to ionotropic N-methyl-D-aspartate (NMDA) and acid (AMPA) receptors promotes excessive calcium influx that triggers a wide array of downstream phospholipases and proteases, which in turn degrade membranes and proteins essential for cellular integrity. In experimental models of stroke, extracellular glutamate levels increase in the micro-dialysate 2, 3 , and glutamate receptor blockade attenuates stroke lesion volumes. NMDA receptor antagonists prevent the expansion of stroke lesions in part by blocking spontaneous and spreading depolarizations of neurons and glia (cortical spreading depression) 4 . More recently, activation of the metabotropic subfamily of receptors has...

Hemicraniectomy for Refractory Edema

Surgical management of ischemic stroke is discussed in further detail in Chapter 6, but worth brief mention here is the use of hemicraniectomy for massive hemispheric cerebral infarction. In patients who are at high risk for herniation, or who are refractory to maximal medical therapy, decompressive hemicraniectomy (DC), with or without partial temporal lobectomy, may be useful in selected patients. DC alleviates tissue shifts and rapidly reduces ICP, allowing for an adequate CPP to perfuse adjacent tissues. DC requires an adequate bone window and duraplasty, as inadequacy of either will leave the patient with a continued restrictive process, and thus continued risk for herniation. Jaeger et al.80 demonstrated a dramatic improvement in brain tissue oxygenation (PtiO2) in patients undergoing craniotomy with decompression for cerebral edematous states, including patients with MCA infarction. Wagner et al.81 found that patients with inadequate hemicraniectomy windows were significantly...

Telestroke In Clinical Practice Networks of Care

FIGURE 10.3 Regional maps depicting TeleStroke Networks. Two hospitals in the TEMPiS network in Bavaria (Germany) provide acute stroke expertise to 12 community hospitals.56 FIGURE 10.3 Regional maps depicting TeleStroke Networks. Two hospitals in the TEMPiS network in Bavaria (Germany) provide acute stroke expertise to 12 community hospitals.56 Gunzburg as part of the Telemedicine in Stroke in Swabia (TESS) Project.33 Of 153 patients examined, 87 were determined to have had an ischemic stroke, but importantly, 40 patients had a diagnosis other than stroke, confirming that teleme-dicine is also helpful in identifying other emergency neurological conditions that may mimic stroke. The duration of teleconsultation was 15 minutes on average. Thirty-seven percent of the 94 patients with ischemic stroke or TIA reached the hospital within 3 hours, and two received thrombolysis. In the opinion of the referring physicians, relevant contributions were made in over 75 of all cases concerning the...

Medical Measures to Control Cerebral Edema

Appears to have a high correlation with serum mannitol levels.56 However, it has yet to be determined what the appropriate osmolar gap should be for the ischemic stroke patient, and thus the repeated administration of mannitol may depend upon what the treating clinician feels is the appropriate gap for that patient, or when they feel that the osmolar gap gives the best approximation for the volume status in the individual patient. In a nonrandomized head-to-head trial of mannitol with hypertonic saline, mannitol appeared to be significantly more effective in improving CPP.57 To date, mannitol has not been subjected to a prospective, randomized trial in space-occupying cerebal infarction, either versus placebo or versus any other osmotic agent. Glycerol is also a nonmetabolizable sugar and is touted to have potential neuroprotective qualities as well. It is not felt to be as potent an osmotic agent as man-nitol. Prior animal studies suggested an effect for rheology and edema...

Stroke Historical Perspectives And Future Directions

The modern period in the history of stroke began in the 1960s when C. Miller Fisher described detailed clinical and pathological observations on the features of lacunar strokes, carotid artery disease, transient ischemic attacks, and intracerebral hemorrhage. His student Louis Caplan established one of the first stroke registry Acute Ischemic Stroke An Evidence-based Approach, Edited by David M. Greer. Copyright 2007 John Wiley & Sons, Inc. databases to collect and analyze important epidemiological, clinical, radiological, and pathological data. Stroke treatment was rudimentary and often nihilistic. Stroke victims might have been treated with maggots or leeches in order to improve blood supply to the brain in hopes of restoring its functions. In 1961, Thomas Dawbe introduced the term ''risk factors'' to describe the contribution of specific conditions to cardiovascular disease. Shortly thereafter, the Framingham heart study highlighted the link between cardiovascular risk factors...

Identifying the Ischemic Penumbra

As discussed above, although irreversible cell death begins within minutes after stroke onset within regions of maximally reduced blood flow (the infarct core), for several hours there exists a surrounding penumbra of ischemic but noninfarcted tissue that is potentially salvageable 134-137 . The concept of an ischemic penumbra provides a rationale for the use of neuroprotective drugs and reperfusion techniques to improve outcome after acute ischemic stroke. However, the extent of penumbral tissue is thought to diminish rapidly with time, hence the therapeutic time window is narrow. With intravenous t-PA the only stroke therapy approved by the Food and Drug Administration (FDA) the window is 3 h, which severely limits its use 138 delayed therapy increases the risk of hemorrhage 115 . Similarly, administering therapy outside of the therapeutic window is considered one of the most important factors leading to the failure of neuroprotective drug trials. Developing methods to rapidly and...

Stroke Neuroprotective Clinical Trials Lessons from Past Failures

Pharmacokinetic properties of the drug, and alterations in cerebral blood flow after stroke need to be taken into account. Blood flow can drop to below 5-10 of normal levels in the infarct core, and to 30-40 of baseline in the surrounding penumbra Given these past failures, the focus has shifted towards expanding the therapeutic time window, improved patient selection, the use of brain imaging as a selection criterion, combination acute stroke drug treatments, use of validated rating scales to assess functional end points, and improved stroke trial design and organization 127,130 . A number of new neuroprotection trials are currently underway or in the planning stages. These include trials of the free radical spin trap agent NXY-059 (now in phase III trials), intravenous magnesium, the antioxidant ebse-len, the AMPA antagonist YM872, and the serotonin antagonist repinotan 131-133 . With the insights gained from prior neuroprotective trials, it is anticipated that one or more of...

Factors Regula3ing Am Gene Expression

With regard to the role of AP-2 in the regulation of AM gene transcription, Nakayama et al. have also reported that phorbol ester, an agonist of diacylglycerol (DAG), induces AM gene expression in human monocytic leukemia cells, and the cis-acting region (-70 to -30) containing multiple AP-2 binding sites is necessary for this induction (Nakayama et al, 2000). As already mentioned, plasma AM is increased in patients with hypertension, heart failure and renal failure (Ishimitsu et al, 1994a Nishikimi et al, 1995 Kato et al, 1999). In the process of cardiovascular disease development, cardiovascular neuroendocrine systems such as the sympathetic nerve system and renin-angiotensin system are activated. Stimulations of cxradrenergic receptor and type 1 angiotensin II (All) receptor both elicit activation of phospholipase C (PLC), production of DAG, activation of protein kinase C (PKC) and induction of AP-2. This pathway may be involved in the mechanism of increased plasma AM in various...

Toshio Nishikimi

The present publication is an up-to-date review of the most relevant aspects of adrenomedullin. It encompasses a broad range of fields, including biochemistry, molecular biology, physiology, pharmacology, pathophysiology of cardiovascular disease, and clinical applications of adrenomedullin to cardiovascular disease. The authors are distinguished colleagues, each one an expert in one or more fields. The cardiovascular system is regulated by many neurohumoral factors, such as the sympathetic nervous system, renin-angiotensin-aldosterone system, natriuretic peptides, endothelin, and vasopressin. The study of these neurohumoral factors has not only enhanced our understanding of the pathophysiology of cardiovascular disease, but has also contributed to improved diagnosis and therapy. In fact, research on neurohumoral factors led to the development of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, aldosterone receptor blockers, endothelin...

Tissue Viability

This section discusses some of the most exciting and technologically complex techniques used in acute stroke imaging those that study brain tissue not just to determine that an ischemic event has occurred in a particular part of the brain, but also to study the viability of ischemic tissue. This has become especially important with the widespread implementation of thrombolytic therapy, which can be very successful in saving brain tissue and dramatically improving outcomes for acute stroke patients, but can also result in catastrophic intracranial hemorrhage. By studying tissue viability, neuroradiologists hope to identify brain tissue that is threatened by ischemia and may be saved by timely reperfusion and to distinguish this tissue from tissue that already has undergone irreversible damage, cannot be saved, and may be at increased risk of hemorrhagic conversion. This helps the patient and the stroke neurologist to understand better the risks and potential benefits of thrombo-lysis...

Conclusion

This chapter has reviewed many of an increasingly wide variety of techniques that are used in imaging the acute stroke patient. The field of acute stroke imaging continues to progress rapidly, driven by the tremendous incidence of the disease, the often devastating nature of its consequences, and the opportunity to make a meaningful difference in the lives of a large number of patients by guiding judiciously the application of increasingly effective stroke therapies, the most widely available of which is intravenous thrombolysis using rt-PA. Advanced CT and MR imaging techniques that show a mismatch between core and penumbra regions have the potential to be critically important tools in selecting patients who may undergo intravenous thrombolysis outside of the currently accepted therapeutic window of 3 hours after stroke onset. Other imaging techniques that are at earlier stages of development may provide even more detailed characterization of tissue viability.

Heart Failure

Artery pressure, plasma renin activity (PRA) and plasma levels of atrial and brain natriuretic peptides (ANP and BNP) (Kato et al., 1996 Kobayashi et al., 1996a). Moreover, according to Etoh et al. (1999), the elevated plasma levels gradually decreased following successful treatment, together with the levels of ANP and BNP, in patients with heart failure. These observational studies suggest an important role for AM in the pathophysiology of heart failure. Kobayashi et al. (1996a) subgrouped forty-nine patients with chronic heart failure based on the primary cause of heart disease, but failed to find any particular heart disease in which plasma AM rises higher than in the others. Therefore, the increased levels appear to be closely related to the degree of depressed cardiac function, not to the primary cause of heart failure. According to Hirayama et al. (1999b) who specifically measured mAM concentrations, plasma levels of mAM and iAM in heart failure patients were similarly elevated,...

Perspectives

The beneficial effects of AM are about to be tested in patients with acute myocardial infarction and in those with pulmonary hypertension. It appears certain that further data will be provided as to the clinical application of AM in diagnosing or treating patients with cardiovascular diseases.

Statins

3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to improve vascular outcomes due to their cholesterol-lowering effects as well as multiple pleiotropic effects.28 In high-risk populations, statin therapy is known to reduce the risk of vascular events such as myocardial infarction and stroke. A meta-analysis of 10 trials involving 79,494 subjects29 showed that statin therapy reduced the incidence of stroke by 18 , major coronary events by 27 , and all-cause mortality by 15 . The SPARCL trial recently showed that high-dose HMG-CoA reductase inhibitors prevent recurrent stroke and transient ischemic attacks.30 In rodent stroke models, statin pretreatment has been shown to reduce infarct volumes and improve outcomes.31,32 Similarly, several clinical studies have shown that prior statin use reduced the severity of acute ischemic stroke and myocardial infarction.33-36 Recent studies indicate that benefit can be achieved even when treatment is...

Conclusions

Patients with acute stroke commonly warrant ICU level of care. The care of the stroke patient in the acute setting is paramount, as they are at high risk for cardiac and pulmonary, and infectious complications, a risk that continues during their ICU stay. Neurocritical Care Units have greatly advanced the care of patients with cerebellar stroke and massive hemispheric stroke, with advances in the evidence to support the use of ICP monitoring, osmotic agents, and hypothermia to treat cerebral edema. Several studies of surgical management of hemispheric stroke are underway, and this technique may prove to be quite useful in certain patient populations. With advances in our understanding of cerebral pathophysiology, our ability to care for critically ill acute stroke patients is likely to improve greatly in the years to come.

Induced Hypertension

The ischemic penumbra shows impaired autoregulation, and appears to be particularly sensitive to blood pressure manipulation. The rationale for using induced hypertension as a stroke therapy is provided by early studies showing that raising mean arterial pressure results in improved cerebral perfusion within the penumbra, and a concomitant return of electrical activity. In animal models of focal cerebral ischemia, induced hypertension therapy was found to augment cerebral blood flow, attenuate brain injury, and improve neurological function 206, 207 . In humans with acute ischemic stroke, a spontaneous increase in blood pressure is common, and neurological deterioration can occur with excessive antihypertensive therapy 208 . Furthermore, a paradigm for induced hypertension for cerebral ischemia exists in the treatment of vasospasm after subarachnoid hemorrhage 209 . Based upon this rationale, recent trials have studied the effect of induced hypertension (using intravenous...

Clot Entrapment

Self-expanding stents are easier to navigate into the intracranial circulation. Moreover, higher rates of recanalization and lower rates of vasospasm and side-branch occlusion were noticed with self-expanding stents than with balloon-mounted stents in a canine model of acutely occluded vessels with clot emboli.89 Successful recana-lization after deployment of the self-expanding Neuroform stent (Boston Scientific Corp., Natick, MA) was recently reported in five acute stroke patients with clots resistant to chemical thrombolytics, balloon angioplasty, GP IIb IIIa inhibitors, and the MERCI retriever.90 Isolated case reports of successful intracranial recanalization with the Neuroform stent have also been reported.91,92 Self-expanding stents with a higher radial force (e.g., WingSpan, Boston Scientific Corp.) will probably play a key role in acute stroke cases related to intracranial atherosclerotic disease.93 Antegrade flow is essential for the maintenance of vascular patency, as...

Summary

Although the efficacy of intravenous rt-PA in ischemic stroke has been established through several studies, the vast minority of stroke patients remain ineligible for thrombolysis. Efforts are underway to find a safe and effective neuroprotective therapy that can be applied to the broader stroke population. Basic science research has elucidated several fundamental pathways of cell death, each providing an array of molecular and biochemical targets for pharmaceutical intervention. Over 85 stroke neuroprotective drug trials have been conducted however, not a single trial has yielded positive results, and consequently the field of stroke neuroprotection is viewed with pessimism. It is important to understand that these clinical trials had several shortcomings, and their failure may not reflect the nonefficacy of neuroprotective drugs. Much knowledge has been gained from prior efforts. The importance of factors such as thorough preclinical testing, proper patient selection, the choice of...

General Icu Measures

Stroke patients who require ICU admission most commonly do so because of concerns of cerebral edema and possible neurological deterioration, and several general measures may be undertaken to minimize the likelihood of developing these complications. Head of bed elevation to 30 helps to reduce ICP and allows for more unimpeded return of venous blood to the heart. Some of the earliest work on head of bed elevation in brain injured patients was by Rosner and Coley,10 who studied 18 patients with ICP elevations, and found that for every 10 of head elevation above the horizontal position the ICP decreased by an average of 1 mm Hg however, the CPP also decreased by an average of 2-3 mm Hg. Adequate hydration and systemic blood pressure are essential to maintaining adequate CPP in this setting. Fan11 systematically reviewed studies of head of bed elevation with brain injuries, showing a consistent reduction in ICP across most studies. Meixensberger et al.12 evaluated the effect of head...

Other Thrombolytics

There have been three large randomized trials of streptokinase in acute ischemic stroke treatment, all of which were terminated early because of increased sICH and mortality in the treatment group (Table 3.1).42-44 There has been a single large randomized trial of the defibrinogenating agent ancrod in acute ischemic stroke. The Stroke Treatment with Ancrod Trial (STAT)45 randomized acute ischemic stroke patients, presenting within 3 hours of symptom onset, to ancrod (n 248) or placebo (n 252). Ancrod is a purified fraction of Malaysian pit viper venom, which induces rapid defibrinogenation by splitting fibrinopeptide A from fibrinogen. It was given as a 72-hour infusion with a rate of 0.082-0.167 IU kg, depending on the pretreatment fibrinogen level, targeting a plasma fibrinogen level of 1.18-2.03 mmol L. The primary endpoint was favorable outcome at 90 days, defined as BI > 95. More patients in the ancrod group, compared to placebo, had a favorable outcome (42 vs. 34 , p 0.04)....

Magnesium

Magnesium is involved in multiple processes relevant to cerebral ischemia, including inhibition of presynaptic glutamate release 180 , NMDA receptor blockade 181 , calcium channel antagonism, and maintenance of cerebral blood flow 182 . In animal models of stroke, administration of intravenous magnesium as late as 6 h after stroke onset, in doses that double its physiological serum concentration, was found to reduce infarct volumes 183, 184 . In pilot clinical studies, magnesium was found to reduce death and disability from stroke, raising expectations that magnesium could be a safe and inexpensive treatment 185 . However, in a large multicenter trial involving 2589 patients, magnesium given within 12 h after acute stroke did not significantly reduce the risk of death or disability, although some benefit was documented in lacunar strokes 131 .Further studies are ongoing to determine whether paramedic initiation of magnesium, by reducing the time to treatment, yields benefit in stroke...

Timing

The timing of CEA after ischemic stroke has been a controversial issue. In 1969, the Joint Study of Extracranial Arterial Occlusion reported 42 mortality after CEA in patients with neurological deficits of less than 2 weeks duration, compared with 5 mortality in patients with more than 2 weeks of symptoms.2,7 Early evidence also demonstrated an increased risk of intracerebral hemorrhage after early CEA in patients with acute stroke.9-11 This led to the conclusion that most complications occurred with early surgical intervention, and resulted in a traditional 4-6 week delay for CEA after an acute stroke. In retrospect, however, there were major problems with patient selection in these earlier reports. Many of the patients More recent reports conclude that early CEA after a nondisabling ischemic stroke can be performed with perioperative mortality and stroke rates comparable to those of delayed CEA. In a subgroup analysis by the North American Symptomatic Carotid Endarterectomy Trial...

Erythropoietin EPO

EPO is considered one of the most promising stroke therapeutic agents. The mechanistic pathways by which EPO provides its neuroprotective effects remain to be fully elucidated however, it is hypothesized that they involve an EPO receptor distinct from that activated in erythropoiesis. EPO has pleiotropic effects it has been shown to cross the blood-brain barrier, protect against ischemia-reperfusion injury by inhibiting apoptosis and hypoxia, and enhance angiogenesis. When directly administered into the brain, EPO reduces neurologic dysfunction in rodent models of stroke, and reduces infarct volumes by 75 when administered systemically up to 3 hours after arterial occlusion. In a small (n 40), randomized, double-blind, placebo-controlled trial of EPO administered intravenously between 2 hours and 40 minutes and 7 hours and 55 minutes after stroke symptom onset, the agent was found to be safe, and treatment correlated with a reduction in NIHSS score between baseline and day 30 after...

Serotonin Agonists

Repinotan or BAYx3702 is a potent 5HT-1a receptor agonist that binds to pre- and postsynaptic serotonin receptors. It is believed to exert neuroprotection directly via G protein-coupled inwardly rectifying potassium channels which hyperpolarize neurons, block glutamate release, and reduce neuronal firing rates.25 In experimental stroke models, it reduces infarct volume when administered up to 5 hours after stroke onset. A phase II trial demonstrated safety, and there was a trend toward beneficial effect on functional outcome at 3 months when started within 6 hours of stroke onset and continued for 72 hours.26 Repinotan is currently being evaluated in several phase III trials including the Repinotan Stroke Study, the Repinotan in Acute Ischemic Stroke trial, and the Repinotan-Randomized Exposure Controlled Trial (RECT). Piclozotan, or SUN N4057, another selective 5HT-1a receptor agonist, has been shown to be neuroprotective in a rat model of transient MCA occlusion.27 Patients are...

Citicoline

Citicoline (cytidine-5'-diphosphocholine or CDP-choline) is an intermediate in the biosynthesis of phosphatidylcholine and is a neuronal membrane stabilizer. Citicoline showed immense promise in animal studies and in several phase II clinical trials. However, a phase III efficacy trial failed to show benefit. Despite this negative result, many believe that citicoline still holds promise as a stroke therapy. This is because in a post hoc analysis, citicoline was found to reduce ischemic lesion growth on diffusion-weighted MRI (DWI) when administered orally within 24 hours of ischemic stroke52, and a meta-analysis of four citicoline trials showed that a good outcome at 3 months was achieved in 25.2 of citico-line-treated patients versus 20.2 of controls (odds ratio OR 1.33 95 confidence interval CI 1.10-1.62 p 0.0034) .53 The International Citicoline Trial on Acute Stroke (ICTUS) is an ongoing study designed to examine the neuropro-tective effects of citicoline on clinical outcome after...

Platelet Inhibition

The GP Ilb-IIIa complex inhibitor Tirofiban has been used as an adjunct to thrombolysis in a number of small case series reports.46 A small transcranial Doppler (TCD) study suggests that it reduces microembolization from unstable carotid plaque.47 In an open pilot study, Tirofiban administered within 9 hours after stroke onset blocked the conversion of ischemic penumbra to mature infarction.48 A phase III study (SETIS) has started recruiting patients to investigate its efficacy versus aspirin within the 6-hour window.

Hyperoxia

Reduced blood supply after ischemic stroke severely decreases the cellular levels of oxygen and consequently disrupts the function of numerous energy-dependent processes that are required to preserve cellular integrity. Increasing brain tissue oxygenation is therefore considered a rational stroke treatment strategy. Oxygen has distinct advantages over pharmaceutical agents it easily diffuses across the blood-brain barrier, acts on multiple cell death pathways, and high doses are well tolerated without major safety concerns, at least when administered for short durations. Brain oxygenation can be increased either by delivering oxygen at high atmospheric pressures using specialized chambers (hyperbaric oxygen therapy or HBO), inhaling high concentrations of oxygen (normobaric oxygen therapy or NBO), and by injecting per-fluorocarbons, synthetic hemoglobins, and aqueous oxygen solutions. HBO has been extensively studied and showed remarkable efficacy in animal studies108-116 however, it...

Initial Assessment

Noncontrast CT scan without hemorrhage or well-established infarct. Acute ischemic stroke symptoms with onset or last known well, clearly defined. Treatment within 6 h of established, nonfluctuating deficits due to Anterior Circulation (carotid MCA) stroke, between 6 and 8 h mechanical treatment (e.g., Concentric Retriever) should be considered. The window of opportunity for treatment is less well defined in posterior circulation (vertebral basilar) ischemia, and patients may have fluctuating, reversible ischemic symptoms over many hours or even days and still be appropriate candidates for therapy. MRI with MRA as well as DWI and PWI has the advantage of providing more complete information on brain parenchymal injury and penumbral tissue at risk. MRI can be particularly helpful in selected difficult cases. Patients who present with seizures at stroke onset (which was a contraindication to IV rt-PA treament in the NINDS trial) should undergo MRI to exclude the possibility of postictal...

Patient Selection

CEA is a proven and effective therapy for preventing stroke in patients with symptomatic, severe carotid artery stenosis causing transient ischemic attacks (TIAs), or nondisabling strokes.2,3 In the setting of an acute stroke, indications for early CEA include a high-grade carotid stenosis, nondisabling symptoms, and a patent intra-cranial ICA. Early CEA is usually not performed in patients with depressed levels of consciousness or severely disabling strokes due to generally poor outcomes.4 While an abnormal computed tomography (CT) scan in patients with minor stroke does not correlate well with perioperative morbidity, a large radiographic infarct (roughly greater than one third of the middle cerebral artery (MCA) territory) is a contraindication to early CEA since these patients are at highest risk of poor outcome related to reperfusion injury and hemorrhagic complications.5-7 Importantly, early CEA is not absolutely contraindicated after recent administration of intravenous tissue...

Inflammation

Inflammation is intricately related to the onset of stroke, and to subsequent stroke-related tissue damage. Inflammation within the arterial wall plays a vital role in promoting atherosclerosis 53,54 . Arterial thrombosis (usually associated with ulcerated plaques) is triggered by multiple processes involving endothelial activation, as well as pro-inflammatory and pro-thrombotic interactions between the vessel wall and circulating blood elements. Elevated stroke risk has been linked to high levels of serologic markers of inflammation such as C-reactive protein 55 , erythrocyte sedimentation rate (ESR), interleukin-6, TNF-a and soluble intercellular adhesion molecule (sICAM) 56 . These events are promoted in part by the binding of cell adhesion molecules from the selectin and immunoglobulin gene families expressed on endothelial cells to glycoprotein receptors expressed on the neutrophil surface. As evidence, reduced ischemic infarction is observed in ICAM-1 knockout mice, and...

Future Directions

Although IV rt-PA is an effective drug for the treatment of acute ischemic stroke, its impact on public health is limited because of the small number of patients eligible for treatment. In order to find more effective therapies and expand the pool of eligible patients, future research on IV thrombolysis for acute ischemic stroke is therefore warranted and has proceeded along the following main directions (1) finding alternative, more effective, IV thrombolytics (2) improving patient selection using advanced imaging to define a radiological surrogate for the core infarct and ischemic penumbra (3) adjunct therapy with other antiplatelet or antithrombotic agents (4) adjunct therapy with mechanical devices, such as ultrasound energy by transcranial Doppler ultrasound, or catheter-based clot retrieval and (5) adjunct therapy with neuroprotective agents. Desmoteplase, a recombinant plasminogen activator, derived from the Desmodus vampire bat salivary plasminogen activator, was evaluated in...

Arteriosclerosis

Active AM secretion with AM mRNA expression was observed in cultured vascular endothelial and smooth muscle cells of rats and humans (Kitamura et al., 2002 Uemura et al., 2002), and as mentioned in the heart failure section, there is a body of evidence supporting production of AM in the human vasculature, which must partly contribute to the plasma AM level (Hirayama et al., 1999a). Kuwasako et al. (1997) found a possible association between plasma AM levels and endothelial damage by comparing the plasma levels of AM with those of endothelin and thrombomodulin, markers of endothelial damage, in patients with cerebrovascular disease. Similarly, in patients with chronic ischemic stroke, the increased plasma AM level was shown to be associated with the degree of carotid atherosclerosis (Shinomiya et al., 2001). Recently, Suzuki et al. (2004) reported that the plasma AM concentration was elevated in

Thromboaspiration

The Possis AngioJet system (Posis Medical Inc., Minneapolis, MN) is arheolytic thrombectomy device that uses high-pressure saline jets to create a distal Venturi suction which gently agitates the clot face. The generated clot fragments are then sucked into the access catheter. At Massachusetts General Hospital, a 5 French Pos-sis AngioJet catheter was used to successfully treat three patients who presented with acute stroke in the setting of ICA occlusion. Patency of the carotid artery was re-established in two patients. In the third patient, the device was able to create a channel through the column of thrombus, allowing intracranial access.97 The Neu-roJet (Posis Medical Inc.) is a smaller, single-channel device, specifically developed to be used in the intracranial circulation. Unfortunately, issues with vessel dissection and inability to navigate through the carotid siphon were noted in a pilot study for acute ischemic stroke, and the trial was discontinued.77,98 Other vortex...

Flow Augmentation

The NeuroFlo device (CoAxia Inc., Maple Grove, MN) is a dual balloon catheter uniquely designed for partial occlusion of the aorta above and below the origin of the renal arteries (Fig. 4.6). Through mechanisms that have yet to be elucidated, this device increases global cerebral perfusion within minutes of balloon inflation, with little or no increase in mean arterial blood pressure. The ongoing Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS) trial is a prospective, controlled, randomized, multicenter trial of NeuroFlo treatment plus standard medical management versus standard medical management in stroke patients with NIHSS scores between 5 and 18, within 10 hours of symptom onset. A second pilot clinical trial, Flo24, will study the effect of perfusion augmentation in patients who present with an MRI PWI-DWI mismatch between 8 and 24 hours after last seen well.