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Stroke occurs when an artery supplying blood to the brain either suddenly becomes blocked or begins to bleed. This may result in part of the brain dying, leading to a sudden impairment that can affect a range of activities such as speaking, thinking, movement and communication.
Symptoms and signs of stroke include one or more of the following:
Common stroke symptoms are the sudden onset of one or more of the following:
In 2009, around 375,800 Australians had had a stroke at some time in their lives. The majority (70%) were aged 65 and over. It is estimated that just over a third (131,100) of Australians with stroke had a disability from their stroke. People with disability resulting from stroke were much more likely to be profoundly limited (always need help) in core activities (56%) than people with other disabilities. In 2010, stroke was the underlying cause of just over 8,300 deaths in Australia—on average, 23 people died from stroke every day. The good news is that the death rate has fallen by around 70% since 1979. However, although the average rate of decline in stroke death rates has accelerated for people aged 55 and over, it has slowed for those aged 35–54. In 2003, stroke accounted for 4.5% of the total burden of disease in Australia.
There are two main types of stroke. An ischaemic stroke (cerebral infraction) is the most common type of stroke that is caused by a blood clot in an artery that supplies blood to your brain. A clot may form in an artery, in the brain itself, or a clot that has formed in a larger artery in your chest or neck that may break away and be carried by the bloodstream to a smaller artery in your brain where it becomes lodged. Clots tend to form in arteries that have become narrowed by the slow build up of fatty material called ‘plaque’ or ‘atheroma’. This gradual clogging process is known as ‘atherosclerosis’, and is the same process that causes coronary heart disease. Haemorrhagic strokes happen when an artery in your brain bursts. They lead to bleeding in your brain and squashing of the tissue around the broken artery. This type of stroke is usually caused by high blood pressure and/or diseases involving the blood vessels in your brain. Ischaemic stroke accounts for about 80% of stroke and haemorrhagic stroke accounts for about 20%.
Non-modifiable risk factors for stroke
Modifiable medical risk factors – HTN, AF, Coronary artery disease, Diabetes, Dyslipidemia, Asymptomatic Carotid Stenosis Modifiable lifestyle risk factors – Cigarette Smoking, Alcohol Consumption,physical inactivity
Table 1 Non-modifiable risk factors for stroke
Risk factor Impact on stroke incidence
Age Doubles for every successive decade after the age of 55 years
Sex 24% to 30% higher in men; however, absolute annual number of women experiencing stroke is higher because women outlive men
2- to 4-fold higher among African Americans and occur at an earlier agea
Geography Higher rates in the Southeastern U.S. (the so-called “Stroke Belt”), especially along the coasts in Georgia and the Carolinas (so-called “Stroke Buckle”).
Race ethnicity 2-fold higher among Hispanics and occur at an earlier agea Higher among Chinesea Heredity Almost 2-fold higher among first-degree relatives. Chromosome 9p21 (proximal to genes CDKN2A and CDKN2B) has been linked to ischemic stroke risk
Hypertension is the most prominent modifiable risk factor for ischemic stroke. Due to its widespread prevalence, depending on age group, the population attributable risk of hypertension for stroke is as great as 40%, and in the INTERSTROKE study, depending on the definition used, hypertension accounted for as great as 50% of the risk of stroke. In fact, the risk of stroke seems to have a continuous association with blood pressure down to levels as low as 115/75 mmHg. In light of this, the national guidelines redefined categories of hypertension so that normal systolic blood pressure is <120mmHg and normal diastolic blood pressure is <80 mmHg. Most recently, it has been suggested that the variability in blood pressure measurements are associated with greater risk of stroke.
Chronic atrial fibrillation (AF) is a strong stroke risk factor. Among individuals >65 years of age, the prevalence of AF is approximately 6%. Because the prevalence of AF rises with age, the attributable risk of stroke due to AF is highest in much older age groups. So, for instance, AF may account for as much as 25% of strokes among persons aged 80 to 89 years. The risk of stroke is approximately 20 times higher among AF patients with valvular disease and five times higher among AF patients with nonvalvular disease compared to patients without AF. Clinical trial and epidemiological data have been used to derive various stroke risk stratification schemes that can be used in clinical practice for AF patients. Of note, outpatient continuous arrhythmia monitoring is increasingly showing that AF may actually be responsible for a higher percentage of unexplained strokes than was previously known.
Individuals with a presence of coronary artery disease have double the risk of stroke compared to patients without coronary artery disease. The attributable risk of stroke due to coronary artery disease is approximately 12%. Coronary artery disease patients with left ventricular hypertrophy have 3 times the risk of stroke, whereas coronary artery disease patients with congestive heart failure have 4 times the risk. Within 5 years of a myocardial infarction, the rate of stroke is 8.1%, and older patients or patients with a cardiac ejection fraction less than 28% are at higher risk of stroke.
A population-based study of more than 14,000 subjects observed that the presence of diabetes was independently related to a greater risk of ischemic stroke. Insulin resistance without the presence of overt diabetes is associated with a greater risk of stroke. In the Atherosclerosis Risk in Communities study, elevated fasting insulin levels in nondiabetics was related to higher risk of stroke (relative risk, 1.19 per 50 pmol/L rise). Furthermore, among nondiabetic subjects in NOMASS, those with elevated measurements of insulin resistance were significantly more likely to have a first ischemic stroke, even after adjusting for other risk factors and the metabolic syndrome. The metabolic syndrome, a constellation of glucose dysmetabolism, obesity, hypertension, and dyslipidemia has been shown to independently confer greater risk of first and recurrent stroke. It is unclear if metabolic syndrome confers a greater risk of first stroke than what one would expect for its components.
Abnormalities in several serum lipid indices have been linked to symptomatic vascular disease. These associations have been particularly robust in regard to coronary artery disease, but at times it is conflicting in regard to stroke. However, many early studies that examined the relationship of lipids with stroke only examined total serum cholesterol levels and did not include stroke subtyping. Not accounting for the heterogeneity of stroke pathophysiology (vs coronary artery disease), likely contributed to the inconsistent findings. Recent studies that have addressed the limitations of prior studies generally have shown an association of elevated serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and nonhigh-density lipoprotein cholesterol with ischemic stroke risk, especially atherosclerotic and lacunar stroke subtypes. Elevated high-density lipoprotein cholesterol was shown to be protective for stroke in NOMASS.
Prevalence of asymptomatic carotid stenosis rises with age, and can be found in more than 50% of individuals 65 years of age or older. Earlier studies found the risk of stroke with asymptomatic carotid stenosis to be approximately 1.3% per year among patients with stenosis less or equal to 75%, and approximately 3.3% annually among patients with stenosis greater than 75%. The “best” medical therapy has changed because the publications of clinical trials have compared carotid endarterectomy with medical therapy for asymptomatic carotid stenosis. The risk of stroke associated with asymptomatic carotid stenosis has fallen significantly during the past 20 years. With contemporary medical therapy, the average annual rate of ipsilateral stroke is estimated to be <1%.
Smoking is associated with reduced blood vessel distensibility/compliance, elevated fibrinogen levels, increased platelet aggregation, decreased high-density lipoprotein cholesterol levels, and higher hematocrit. The relative risk of stroke for smokers included in a large meta-analysis was 1.5, and a dose-response association with higher stroke risk has been observed in heavy vs light smokers. Roughly 18% of strokes are attributable to active cigarette smoking. Stroke risk associated with former smoking has been shown to substantially decrease with increasing time because of cessation, and the Framingham study found stroke risk to be at the level of nonsmokers at 5 years from cessation. Even passive cigarette smoking boosts progression of atherosclerosis. Indeed, there is a greater risk of ischemic stroke among cigarette-smoking women with a cigarette-smoking spouse vs those with a nonsmoking spouse. Finally, smoking modifies the influence of oral contraceptives on stroke risk, as there seems to be a 7-fold rise in risk among persons who both smoke and use oral contraceptives.
Heavy alcohol consumption is associated with elevated blood pressure, enhanced coagulability, cardiac arrhythmias, and decrease in cerebral blood flow. On the other hand, light-to-moderate consumption has been linked to elevated high-density cholesterol and endogenous tissue plasminogen activator levels. Increasing alcohol consumption is associated with greater risk of hemorrhagic stroke in a dose-dependent manner. However, studies evaluating the impact of alcohol consumption on ischemic stroke risk have not shown consistent results. Indeed, the majority of published evidence points to a protective effect of light-to-moderate drinking (1-2 drinks per day) on the risk of ischemic stroke including data from the Nurses’ Health Study and NOMASS (adjusted odds ratio, 0.5).
Increased physical activity is associated with reductions in fibrinogen, homocysteine, and platelet activity, as well as elevations in high-density lipoprotein cholesterol and plasma tissue plasminogen activator activity. Observational data show that physical activity is linked with lower stroke risk, whereas sedentary behavior is related to higher stroke risk. A meta-analysis of 23 studies that examined the relationship of physical activity with risk of stroke noted that highly active subjects experienced a 27% lower risk of stroke or mortality vs low-active subjects.
Primary prevention is aimed at reducing the risk of stroke in asymptomatic people. The most effective prevention is through control of modifiable risk factors. Adequate blood pressure reduction, cessation of cigarette smoking and use of antithrombotic therapy in atrial fibrillation are the most effective measures. Carotid endarterectomy may be useful in selected patients. Although very useful for health in general, tight control of diabetes and hypercholesterolemia, physical exercise and alimentary diet did not show a major influence for primary stroke prevention. Aspirin seems to be not very effective for primary stroke prevention, whereas some ACE inhibitors (e.g. ramipril), ARBs (e.g. losartan) or statins, may have a preventive role beyond their antihypertensive or hypocholesterolemic properties.
Secondary stroke prevention is aimed at reducing the risk of recurrence after a first stroke or transient ischemic attack. Acting on risk factors is probably as effective as in primary prevention. Carotid endarterectomy for symptomatic stenoses > 70% and anticoagulation in patients with atrial fibrillation are by far the most effective measures. Antiplatelet therapy (aspirin, ticlopidine, clopidogrel and long acting dipyridamole-aspirine association) reduces significantly stroke recurrence. Most recent data suggest also that perindopril, eprosartan and some statins are beneficial against stroke recurrence even in normotensive and normocholesterolemic patients.
When used to treat stroke, thrombolysis is described as the injection of a chemical agent into the veins, which significantly reduces the risk of death or complication in patients with ischaemic stroke. Patients need to meet certain criteria to be eligible for this treatment. These criteria include the patient’s age, the time from stroke onset to injection and the type of stroke. Tissue plasminogen activator was licensed in October 2003 by the Australian Therapeutic Good Administration for use in a 3-hour window for patients with ischaemic stroke, but, based on further evidence, this window has been extended to 4.5 hours (National Stroke Foundation 2010).
Thrombolysis is not captured comprehensively in the NHMD because its collection is not mandated in the Australian Coding Standard. Furthermore, thrombolysis is more likely to be administered in an emergency department before, rather than after, hospital admission, and when it is performed after admission it is not possible to identify when stroke-specific rt-PA has been used.
In 2009–10, less than 1% of hospitalisations for stroke were recorded to have had thrombolytic agents administered.
For many decades, intravenous (IV) thrombolytics have been delivered to treat acute thrombosis. Although these medications were originally effective for coronary thrombosis, their mechanisms have proven beneficial for many other disease processes, including ischemic stroke. Treatment paradigms for acute ischemic stroke have largely followed those of cardiology. Specifically, the aim has been to recanalize the occluded artery and to restore perfusion to the brain that remains salvageable. To that end, rapid clot lysis was sought using thrombolytic medicines already proven effective in the coronary arteries.
IV-thrombolysis for ischemic stroke began its widespread adoption in the late 1990s after the publication of the National Institute of Neurological Disorders and Stroke study. Since that time, other promising IV-thrombolytics have been developed and tested in human trials, but as of yet, none have been proven better than a placebo. Adjunctive treatments are also being evaluated. The challenge remains balancing reperfusion and salvaging brain tissue with the potential risks of brain hemorrhage.
Physiology of Thrombolysis The term thrombolytic is usually synonymous with fibrinolytic. In the setting of ischemic stroke, this term specifically relates to degradation of fibrin, the tough netlike backbone of a clot that is blocking flow to a portion of the brain. The clot can form in-situ or can travel from another source, such as a tight carotid stenosis or the heart. From a clinical standpoint, a thrombolytic is a drug that is delivered for the purpose of recanalization of the occluded artery and reperfusion of ischemic, but still salvageable brain tissue. If reperfusion is begun early enough and blood supply is renewed to the brain territory devoid of oxygen supply, the tissue can be salvaged and resultant damage can be lessened
Thrombolytic Drugs Efficacy of thrombolytic drugs depends on a few important factors: 1) the age of the clot can reduce the efficacy of the thrombolytic, and older clots tend to have more fibrin crosslinking and are more resistant to thrombolytics. 2) the specificity of the lytic for fibrin will determine its activity, and other determinants of efficacy include half-life and the presence of any neutralizing antibodies.
Thrombolytics can be divided into two different categories: 1) fibrin-specific thrombolytics and 2) nonfibrinspecific thrombolytics. Some examples of fibrin-specific drugs are: alteplase, reteplase, and tenecteplase. Nonfibrinspecific drugs include streptokinase or staphylokinase. Alternatively, lytics that convert plasminogen into plasmin can be described as direct versus indirect. Direct activators are the same as those previously listed for fibrin-specific drugs. Indirect activators of plasminogen include streptokinase, staphylokinase, and desmoteplase (vampire bat plasminogen activator). Direct activators are all serine proteases that cleave a single (arginine-valine) amino acid bond to yield plasmin. Indirect activators are not proteolytic, but rather form a complex with plasminogen which can then convert additional plasminogen to plasmin. More recently, the testing of plasmin itself has been under development. The half-life of plasmin is very short; when administered by IV, plasmin is rapidly neutralized by α2-anti-plasmin, and it does not dissolve the thrombus or induce bleeding. Thus, plasmin is better suited as a local agent.
IV thrombolysis remains the only proven medical treatment for reducing the disability caused by acute ischemic stroke. However, the time window of opportunity for treatment is still narrow as the majority of patients with ischemic stroke do not receive thrombolysis, and complete clot lysis occurs in the minority of patients . Ongoing clinical trials aiming to improve rates of recanalization widen the treatment window or broaden eligibility so that more patients can benefit. Regardless of what new thrombolytic or adjunctive treatment, if any, is discovered to be effective for future stroke sufferers, it remains absolutely crucial that patients are transferred fast to stroke centers. In wellorganized stroke centers, it is possible to reach 20 minutes door to IV t-PA needle time .
Stroke is a leading cause of death and disability. Recently, there have been advances in the treatment of acute ischemic stroke aimed at re-establishing blood flow to the affected area in an effort to save the ischemic penumbra surrounding the area of infarction. This is achieved by the use of thrombolytics intravenously or intra-arterially. The use of mechanical devices facilitates the function of pharmacological agents used in addition to minimizing the associated risks. In this review, we first discuss the therapeutic potentials and strategies employed in using different thrombolytics in management of acute ischemic stroke. Subsequently, we discuss the recent advances and therapeutic applications of mechanical devices in this field.
An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. Currently, the only approved medical therapy for acute ischemic stroke is tissue plasminogen activator (tPA), a thrombolytic agent that targets the thrombus within the blood vessel.
Despite the availability of thrombolytic therapy, stroke is the fourth leading cause of death in the world and a leading cause of adult disability. To reduce the devastating impact of stroke on society, physicians continue to seek ways to achieve better functional recovery in stroke patients.
Neuroprotective agents, another approach to stroke treatment, have generated long-term interest. Neuroprotective agents are used in an attempt to save ischemic neurons in the brain from irreversible injury. Studies in animals indicate a period of at least 4 hours after onset of complete ischemia in which many potentially viable neurons exist in the ischemic penumbra. In humans, the ischemia may be less complete, and the time window may be longer, but human patients also tend to be older, with comorbidities that may limit benefit. Because many neuroprotective drugs reduce ischemic damage in animal models of stroke, this line of pharmaceutical research hold promise despite the lack of efficacy in human models to date. Many investigators are searching for a safe agent that can limit ischemic damage in human stroke. One action of neuroprotective agents limits acute injury to neurons in the ischemic penumbra. Neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury.
Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury. Returning blood contains leukocytes that may occlude small vessels and release toxic products.
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