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Acute Ischemic Stroke Update

Kathleen Baldwin, Pharm.D.; Sean Orr, M.D.; Mary Briand, Pharm.D.; Carolyn Piazza, Pharm.D.; Annita Veydt, R.N.; Stacey McCoy, Pharm.D. Posted: 06/24/2010; Pharmacotherapy. 2010;30(5):493514. 2010 Pharmacotherapy Publications

Abstract and Introduction

Abstract Stroke is the third most common cause of death in the United States and is the number one cause of long-term disability. Legislative mandates, largely the result of the American Heart Association, American Stroke Association, and Brain Attack Coalition working cooperatively, have resulted in nationwide standardization of care for patients who experience a stroke. Transport to a skilled facility that can provide optimal care, including immediate treatment to halt or reverse the damage caused by stroke, must occur swiftly. Admission to a certified stroke center is recommended for improving outcomes. Most strokes are ischemic in nature. Acute ischemic stroke is a heterogeneous group of vascular diseases, which makes targeted treatment challenging. To provide a thorough review of the literature since the 2007 acute ischemic stroke guidelines were developed, we performed a search of the MEDLINE database (January 1, 2004July 1, 2009) for relevant English-language studies. Results (through July 1, 2009) from clinical trials included in the Internet Stroke Center registry were also accessed. Results from several pivotal studies have contributed to our knowledge of stroke. Additional data support the efficacy and safety of intravenous alteplase, the standard of care for acute ischemic stroke since 1995. Due to these study results, the American Stroke Association changed its recommendation to extend the time window for administration of intravenous alteplase from within 3 hours to 4.5 hours of symptom onset; this recommendation enables many more patients to receive the drug. Other findings included clinically useful biomarkers, the role of inflammation and infection, an expanded role for placement of intracranial stents, a reduced role for urgent carotid endarterectomy, alternative treatments for largevessel disease, identification of nontraditional risk factors, including risk factors for women, and newly published pediatric stroke guidelines. In addition, new devices for thrombolectomy are being developed, and neuroprotective therapies such as the use of magnesium, statins, and induced hypothermia are being explored. As treatment interventions become more clearly defined in special

subgroups of patients, outcomes in patients with acute ischemic stroke will likely continue to improve.

Acute Ischemic Stroke Update

Stroke is the number one cause of adult disability in the United States and Europe and is the third leading cause of death in the United States. Approximately 15% of strokes are hemorrhagic and 85% are ischemic.[1] Acute ischemic stroke (AIS) is a heterogeneous group of vascular diseases that encompasses large-artery atherosclerosis (16.3%), penetrating small-artery disease (lacunar infarcts, 15.9%), cardiogenic embolism (29.1%), stroke of unknown etiology (36.1%), and stroke of other determined etiology (2.6%).[2] A stroke may occur in the arterial or venous vasculature and may be due to either intracranial or extracranial disease. Large-artery strokes may result from atherogenic embolus or hypoperfusion. These strokes may manifest with large clot burdens and more severe baseline neurologic deficit and, as a consequence, may fail traditional AIS interventions.[1] Malignant middle cerebral artery (MCA) occlusions represent a special subtype of large-artery strokes, the manifestation of which differs from that of other AIS cases.[3] Recent clinical trials focusing on alternative interventions have provided new information about successful recanalization strategies in large-vessel occlusions.[4] Cardiogenic embolism may result from an atrial or ventricular thrombus as a consequence of atrial fibrillation, atrial flutter, mechanical or prosthetic heart valves, recent myocardial infarction, or cardiomyopathy.[1] Iatrogenic causes of cardiogenic stroke include cardiac catheterization, coronary artery bypass surgery, percutaneous transluminal coronary angioplasty or valvulplasty, intraaortic balloon pump, or cardiac transplantation. Lacunar infarcts are distinctive in the stroke classification scheme because they do not require demonstration of a vascular lesion.[1] Also, these infarcts may be the result of hypertension, diabetes mellitus, dyslipidemia, or genetic disorders, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencepahlopathy (CADASIL), which is an autosomal dominant mutation on the NOTCH3 gene in chromosome 19 that results in thickening of the muscular wall of small blood vessels typically in white matter of brain.[5] Stroke of other determined etiology includes nonatherosclerotic vasculopathies, prothrombotic states, dissections, paradoxic embolization through a patent cardiac septal defect, illicit drug use, and autoimmune disorders. This classification of AIS cases includes those with multiple causes or no probable evidence to be able to establish a single cause. The American Heart AssociationAmerican Stroke Association (AHA-ASA) AIS treatment guidelines were updated in 2007; however, several important

contributions have been made since that time.[3] These include the recommendation from AHA-ASA to expand the physiologic window of time for administration of intravenous alteplase from 3 to 4.5 hours, newly identified clinically useful biomarkers, a new focus on the role of inflammation and infection in AIS, neuroprotective strategies, an expanded role for intracranial stent placement, a reduced role for urgent carotid endarterectomy, identification of nontraditional risk factors, including risk factors for women, alternative interventions in the treatment of large-vessel disease, and newly published pediatric stroke guidelines.[612] To increase our knowledge of current drug therapies and new developments in the treatment of AIS in adults, we conducted a literature search of the MEDLINE database (January 1, 2004July 1, 2009), for relevant English-language studies, by using the following terms: acute ischemic stroke, alteplase, recombinant tissuetype plasminogen activator, rtPA, drug therapy for ischemic stroke, neuroprotection, and malignant middle cerebral artery occlusions. Results (through July 1, 2009) from clinical trials included in the Internet Stroke Center registry were also accessed. This information as well as legislative efforts that have resulted in major contributions to the treatment of AIS are presented.

Risk Factors
Stroke affects people of all ages and race-ethnicities and of either sex. It may be over-looked in patients younger than 50 years. Nonmodifiable risk factors include advanced age, male sex, African-American race, previous stroke, or history of stroke or heart disease in family members aged younger than 60 years.[13] Modifiable risk factors include hypertension, diabetes, hypercholesterolemia, metabolic syndrome, smoking, hyperhomocysteinemia, sleep apnea, and illicit drug use. Additional risk factors for women include pregnancy, use of oral contraceptives with an increased risk when combined with smoking, use of hormone replacement therapy, and association with migraine with aura.[1416] Risk assessment tools such as the Framingham Risk Assessment and the CHADS2 (cardiac failure, hypertension, age, diabetes, stroke [doubled]) scores are useful predictors of a risk for coronary artery disease, as well as for predicting stroke risk.[13, 17] The Framingham Risk Assessment was developed from the Adult Treatment Panel III and assesses patient age, sex, blood pressure, cholesterol levels, and smoking status to estimate a 10-year risk of developing coronary heart disease. The CHADS2 score has utility in patients with atrial fibrillation and examines for presence of previous stroke or transient ischemic attack, diabetes, age older than 75 years, hypertension, and heart failure for determining the risk of stroke.[17] These risk estimators of coronary heart disease and stroke can help tailor preventive therapies for patients. Viral infections, most notably influenza, in addition to bacterial infections appear to be an inflammatory trigger that may precede up to one third of ischemic

strokes.[18] The highest stroke risk appears to occur within 1 week of an acute infection, and the severity and clinical outcome of AIS may be worse when preceded by an infection. Both acute and chronic infections may increase inflammation biomarkers such as C-reactive protein and interleukin-6 and may represent future areas of targeted therapies for AIS in the presence of infection.[18] Other inflammatory biomarkers including interleukin-6, tumor necrosis factor, C-reactive protein, and fibrinogen are associated with recurrence of stroke.[18, 19]

Symptoms
Rapid recognition of stroke symptoms is paramount because "time lost is brain lost," and several interventions require strict adherence to timelines that begin at symptom onset. The five cardinal signs of stroke include weakness, speech impairment, vision impairment, headache, and dizziness.[20] Vision impairments commonly involve a sudden loss of vision usually in one eye or double vision. Sudden severe and unusual headache (often referred to as a "thunderclap" headache), described as the worst headache of one's life, is most often associated with hemorrhagic stroke (particularly subarachnoid hemorrhage). Dizziness may be accompanied by sudden loss of balance and may result in a fall.[20]

Emergency Management
Emergency Medical Services In addition to educating patients on how to identify symptoms of stroke, pharmacists should counsel patients that immediate activation of emergency medical services at the onset of stroke symptoms is critical. The activation of emergency medical services results in faster hospital arrival, decreased time to initial physician assessment, and expedited diagnostic testing.[21] It is important to establish intravenous access, initiate crystalloid therapy, and evaluate the patient's glycemic status, as symptoms of hypoglycemia may mimic those of AIS. Immediate transfer to the nearest urgent care center capable of treating patients with AIS is paramount.[22] Stroke Centers The AIS stroke guidelines adopted the recommendation by the Brain Attack Coalition for the establishment of two designations of stroke centers: primary stroke centers and comprehensive stroke centers.[3, 22] The Florida Stroke Act of 2004 requires that patients experiencing a stroke be transported by emergency medical services to a certified stroke center.[23] One recent study applied a pragmatic stroke system model to improve outcomes of intravenous alteplase therapy in a community hospital supported by a regional stroke system.[24] The authors reported that these outcomes at the stroke center showed a reduced rate of symptomatic intracranial hemorrhage of 3.3% compared

with 6.4% in emergency department settings in the original National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator (rt-PA) Stroke Trial. In addition, it was reported that 3-month modified Rankin Scale[25] (mRS; a scoring system for measuring disability) scores of 01 (indicating no to minimal disability; scores of 56 indicate severe disability or death) were 54% versus 43% in the NINDS rt-PA trial (p=0.04). Mortality rates were 13% at the stroke center versus 17% in the NINDS rt-PA trial. In addition to stroke centers, teleneurology systems are being developed to reach patients with AIS in rural areas who may not otherwise have access to a stroke neurologist.[26] Patient Evaluation and Management in the Emergency Department According to data published by the Paul Coverdell National Acute Stroke Registry, nearly 50% of patients in the registry who experienced a stroke came to an emergency department within 2 hours of symptom onset.[21] Thus, the establishment of protocols for the emergency triage and management of patients with acute stroke is critical.[3] Patients should be evaluated and decisions on treatment made within 60 minutes of patient arrival to the emergency department. Patients must receive airway, breathing, and circulatory assessment followed by a neurologic evaluation. Determining the time of onset of stroke symptoms is imperative. Patient assessment with use of the National Institutes of Health Stroke Scale (NIHSS)[25, 27] and mRS[25] may be conducted by nurses certified in this process to determine stroke deficits (Figure 1). The NIHSS evaluates neurologic impairment on a scale of 142, with higher scores indicating severe neurologic impairment and lower scores less severe impairment. Any baseline score other than zero warrants neurologic work-up. These standardized scales may provide outcome assessments when performed at presentation, 24 hours after admission, and again at discharge. All patients with stroke must be screened for dysphagia. Failure to screen may result in oral drugs being inappropriately administered and result in aspiration pneumonia.[3]

Figure 1. Sample of a form for assessing patients with the use of the National Institutes of Health Stroke Scale[27] and modified Rankin Scale.[25]

As part of the acute stroke pathway, a number of diagnostic tests should be performed including blood glucose level, serum electrolyte level, complete blood cell count, platelet count, renal function studies, prothrombin time, activated partial thromboplastin time, oxygen saturation, and cardiac markers.[3] Patients should receive continuous oxygen therapy with oxygen saturation and cardiac monitoring. Those presenting with a cardiac history should undergo electrocardiography since patients with stroke of thromboembolic origin may have acute myocardial infarction as well; however, management of these patients is outside the scope of this article.

Biomarkers
The role of plasma biomarkers in AIS is under investigation. N-Methyl-Daspartate receptor autoantibodies may be detectable in plasma during AIS and play a vital role in the ischemic cascade.[28] Other proteins involved in brain ischemia include astroglial protein S100B, B-type neurotrophic growth factor, von Willebrand factor, and matrix metalloproteinase (MMP)-9. Inflammatory biomarkers associated with the acute-phase response of AIS include interleukin-6, tissue necrosis factor-, C-reactive protein, and fibrinogen.[19] One predictive biomarker model included brain natriuretic peptide, C-reactive protein, D-dimer, MMP-9, and S100B, and a sensitivity of 81% and specificity of 70% for diagnosing AIS were reported.[7] Biomarkers such as MMP-9 and ferritin may have additional utility in predicting hemorrhagic complications after fibrinolytics and in identifying patients at risk for developing complications.[7, 29] The presence of plasma MMP-9 is known to play a deleterious role in AIS due to its ability to degrade laminin and fibronectin, important components of the blood-brain barrier. Animal studies show that during cerebral ischemia, free iron is released from intracellular stores and catalyzes the conversion of superoxide and hydrogen peroxide into a highly toxic hydroxyl radical contributing to higher oxidative stress and inflammation.[29] In humans, baseline ferritin levels greater than 79 ng/ml before administration of intravenous alteplase increased hemorrhagic transformation and cerebral edema.[29] The presence of plasma MMP-9 and high ferritin levels have been demonstrated to be an independent predictor of hemorrhagic transformation in patient with AIS.[7, 29] Urgent brain imaging should be conducted with use of computed tomography (CT) without contrast material enhancement, which is the current gold standard used to differentiate hemorrhagic causes of neurologic injury from nonvascular injury to the brain. This provides the clinician with information regarding size, location, and vascular distribution of the infarct. The differential diagnosis for AIS includes ruling out migraine, hemorrhagic stroke, head trauma, brain abscess, encephalitis, brain tumor, seizure with postictal paralysis, and hypoglycemia.

Goals of Therapy
For all interventions performed urgently in patients with AIS, the goals are limiting the area of ischemia (infarct) and salvaging the penumbra. The penumbra is a hypoperfused area of focal ischemia that is potentially viable and may be salvaged by timely and appropriate intervention, including maintenance of euvolemia.[3] Once the patient is stable, the goal of AIS therapy is to remove the occlusion through recanalization. When contraindications to removing the occlusion are present, preventing extension of the infarct becomes critical.

Intravenous Alteplase
The administration of rt-PA, a fibrinolytic agent used to remove the occlusion, remains one of the few class I, level of evidence A drug therapy recommendations in the treatment of AIS.[3] Administration should be considered only if the benefit outweighs the risk and no exclusion criteria exist. Absolute contraindications to the use of intravenous alteplase for acute ischemic stroke include the following:

Evidence of intracranial hemorrhage on pretreatment evaluation Suspicion of subarachnoid hemorrhage on pretreatment evaluation Recent (within 3 mo) intracranial or intraspinal surgery, serious head trauma, or previous stroke History of intracranial hemorrhage Uncontrolled hypertension at time of treatment (> 185 mm Hg systolic or > 110 mm Hg diastolic blood pressure) Seizure at the onset of stroke Active internal bleeding Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis including but not limited to the following: Current use of oral anticoagulants (e.g., warfarin sodium) or an international normalized ratio greater than 1.7 or a prothrombin time greater than 15 seconds Administration of heparin within 48 hours before the onset of stroke and an elevated activated partial thromboplastin time at presentation Platelet count less than 100 x 103/mm3

Alteplase, a tissue plasminogen activator, is an enzyme that can convert plasminogen to plasmin as a result of fibrin enhancement. At pharmacologic concentrations, it binds to fibrin within the thrombus, forming an active lytic complex. The recommended alteplase dose for patients with AIS is 0.9 mg/kg (maximum 90 mg), with a bolus of 10% of the dose administered over 1 minute, and the remainder infused over 60 minutes.[3, 30] Significant drug interactions may occur with concomitant administration of anticoagulant and antiplatelet agents, both of which increase the bleeding risk. The greatest risk of treatment with alteplase is symptomatic intracranial

bleeding.[3, 30] Therapeutic heparin, antithrombotics, and anticoagulants are contraindicated within 24 hours after administration of alteplase. Mechanical prevention of deep vein thrombosis traditionally has been preferred over medical prevention; however, the recently conducted European Cooperative Acute Stroke Study (ECASS) III used subcutaneously administered heparin at a daily dose of 10,000 units or less without increased bleeding complications.[6] Postmarketing studies report the presence of laryngeal and orolingual angioedema to be less than 1%, but this life-threatening situation may require urgent airway stabilization. An observational study found that the frequency of orolingual angioedema was 1.7% (95% confidence interval [CI] 0.25.9%) with angiotensinconverting enzyme (ACE) inhibitor therapy as a risk factor.[31] As plasminogen is converted to plasmin, the plasmin cleaves bradykinin from high-molecular-weight kininogen.[32] This coupled with an ACE-inhibitormediated decrease in bradykinin metabolism along with increased neurokinin levels might explain the increased risk. The NINDS rt-PA trial established safety and efficacy of alteplase administered within 3 hours of symptom onset; this study has become the gold standard to which all other intravenous fibrinolytic AIS studies are compared.[33] However, a delay in reporting of symptoms and transport to an emergency department are the largest hindrances to the administration of intravenous alteplase. The recently published results of the ECASS III study showed the safety and efficacy of an expanded physiologic time window from 3 to 4.5 hours in patients with mild-tomoderate AIS.[6] This study, in light of other clinical trials, a recent meta-analysis, and stroke registry data, resulted in the AHA-ASA recommendation to expand the time window from 3 to 4.5 hours in a valid AIS population.[34] In addition to the expanded time window, the AHA-ASA cautions that application of similar exclusion criteria must be used in the clinical setting, citing no proven benefit in patients excluded from the ECASS III study.[34] The committee made another recommendation cautioning that the expanded time window should not be interpreted as a reason to relax the sense of urgency with patients with AIS.[34] Efficacy The NINDS rt-PA study was a multicenter, placebo-controlled study that enrolled 624 patients with AIS from January 1991October 1994.[33] Patients received either intravenous alteplase 0.9 mg/kg (maximum 90 mg) as a bolus of 10% of the dose administered over 1 minute followed by the remainder or placebo as a 1-hour infusion within 3 hours of symptom onset. It was conducted in two parts; the primary end point of part 1 included a comparison of the proportion of patients with neurologic improvement as defined by an increase of 4 or more points on the NIHSS score or resolution of neurologic deficit at 24 hours after stroke onset based on time to treat (090 min, 90180 min). The results of part 1 indicated no statistically significant differences between groups in the primary end point (67

patients [47%] in the treatment group vs 57 patients [39%] in the placebo group, p<0.21). The median NIHSS scores at 24 hours were 8 (range 317) in the treatment group and 12 (range 619) in the placebo group. Part 2 of the trial evaluated the global odds ratio (OR) from combined scales by using the Barthel Index, mRS, Glasgow Outcome Scale (GOS), and NIHSS for favorable outcomes at 90 days.[25] The Barthel Index is a 100-point scale, with higher scores correlating with high levels of independence in activities of daily living. The GOS is a measure of functional recovery, with 1 indicating death and 5 indicting good recovery. All four scales indicated statistically significant improvements in 90-day outcomes in the treatment group compared with the placebo group. Final analysis indicated that treated patients were at least 30% more likely than those in the placebo group to have minimal or no disability at 90 days. One strength of the NINDS rt-PA study is early treatment with intravenous alteplase, as most patients received the drug within 090 minutes for part 1 (51%) and part 2 (59%). In addition, protocol adherence was high (> 90%) in both parts. The NINDS rt-PA study demonstrated that intravenous alteplase improved 90-day outcomes when administered early and when protocols were followed. The rt-PA (Alteplase) 0- to 6-Hour Acute Stroke Trial, Part A (A0276g) was a phase II trial that began in August 1991.[35] This trial was designed to assess the efficacy and safety of intravenous alteplase in patients with AIS who were treated within 6 hours of symptom onset. The mean time to treatment was 4 hours 24 minutes in the treatment group versus 4 hours 17 minutes in the placebo group (p=0.55). Only 17% of patients in the placebo group and 14% of those in the alteplase group were treated within 3 hours of symptom onset, whereas 34% and 31%, respectively, were treated between 5 and 6 hours. This phase II trial was stopped prematurely due to an increased frequency of adverse events in the 56-hour group. The inclusion criteria were revised to reduce the time to treatment from symptom onset to 5 hours. The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study was the phase III, randomized, placebo-controlled trial of the A0276g trial that excluded patients treated 56 hours after symptom onset.[36] It was conducted from December 1993 through July 1998. This trial evaluated efficacy and safety of intravenous alteplase administered within 35 hours of symptom onset compared with placebo in both an intent-to-treat (ITT) and per-protocol analysis. The mean time to intravenous alteplase administration was 4 hours 28 minutes. Primary efficacy was defined as excellent neurologic recovery at day 90 (NIHSS score of 0 or 1); secondary efficacy end points included excellent recovery on functional outcome measures (Barthel Index, mRS, and GOS) at 30 and 90 days. The primary efficacy end point was not statistically significant in either analysis.[36] The only efficacy end point reached was an improvement of NIHSS

scores by greater than 11 points in the treatment group in both analyses at 30 days and the per-protocol analysis at 90 days, although this effect did not lead to an excellent overall recovery. The researchers determined that because this was the only positive finding out of 25 efficacy variables, a type I error due to multiple comparisons may have occurred. The ATLANTIS trial was deemed to be a negative trial like its earlier counterpart. The first ECASS trial was a multicenter, randomized, placebo-controlled trial that recruited patients between late 1992 and early 1994.[37] Patients were randomly assigned to receive intravenous alteplase 1.1 mg/kg or placebo within 6 hours of stroke symptom onset, with use of ITT and per-protocol analyses. Primary end points included mRS and Barthel Index scores at 90 days, neither of which reached statistical significance. A total of 109 patients (17.4%) were excluded from the per-protocol analysis because of major protocol violations. The main contributions of this study are discussed later in the alteplase safety section. The ECASS II trial was a randomized, double-blind, placebo-controlled trial of thrombolytic therapy with intravenous alteplase in patients with AIS who were recruited between October 1996 and January 1998.[38] Patients who presented within 03 hours or within 36 hours of symptom onset were included in the study. The dose of intravenous alteplase 0.9 mg/kg was administered as in the NINDS rt-PA study. Greater than 80% of the study population was enrolled in the 36-hour window group (326 patients in treatment group), with the average time to treatment of 4.3 hours, leaving a small sample in the 03-hour group (81 patients in treatment group). The median baseline NIHSS scores were 11 in both groups. The primary end point was the proportion of patients who had a favorable mRS score (01) compared with an unfavorable mRS score (26) at 90 days by using an ITT analysis. The results indicated a statistically insignificant improvement in the treatment group; however, there was an imbalance between the numbers in the two groups (407 patients in the treatment group vs 386 in the placebo group), leading the authors to conclude that the results may have been due to a type II error. The Safe Implementation of Thrombolysis in StrokeMonitoring Study (SITSMOST) was an observational study that evaluated 6483 patients who received intravenous alteplase within 3 hours of symptom onset between December 2002 and April 2006; outcomes at experienced stroke centers were compared with those of less experienced hospital settings.[39] The study was designed to assess the safety of alteplase in clinical practice by comparing the results from 285 centers (50% of these centers had little or no experience with the drug) to study results from previously completed randomized controlled trials. The primary outcome was safety and thus is discussed later. One efficacy parameter was evaluated: the degree of functional independence as defined by mRS score of 02 at 90 days. This outcome was achieved in 3362 (54.8%, 95% CI 53.556%) of the 6136 patients available for follow-up. The pooled analysis of the more experienced centers indicated 227 (49%, CI 95% 44.453.6%) of 463 patients had achieved an

mRS score of 02 at 90 days. An absolute difference of 5% was noted between the two groups in favor of the less experienced centers. One contribution of this study was that smaller, less experienced centers may see similar efficacy as that in larger more experienced centers. The ECASS III trial was conducted between July 2003 and November 2007 and evaluated intravenous alteplase administration between 3 and 4.5 hours after symptom onset.[6] This study used ITT and per-protocol analyses. Strict inclusion and exclusion criteria were followed. Exclusion criteria included severe stroke (NIHSS score 25), combination of previous stroke and diabetes, and traditional contraindications to intravenous alteplase use. The primary efficacy end point was disability, dichotomized as a favorable outcome (mRS score 01) or an unfavorable outcome (mRS score 26) at 90 days. Of the 418 patients in the extended intravenous alteplase window group, the median time for administration was 3 hours 59 minutes. More patients had a favorable outcome with alteplase in both analyses. When compared with placebo, 219 patients (52.4%) in the treatment group reached the primary end point of mRS score 01 at 90 days compared with 182 patients (45.2%) in the placebo group (OR 1.34, 95% CI 1.021.76, p=0.04) in the ITT analysis. The perprotocol analysis indicated that 206 patients (54.9%) in the treatment group versus 161 patients (45.4%) in the placebo group reached an mRS score of 01 with a reported OR of 1.47 (95% CI 1.101.97, p<0.01). The secondary end point of the trial evaluated the global OR from combined scales by using the Barthel Index, mRS, GOS, and NIHSS assessed at 90 days. Both end points demonstrated a statistically significant improvement in outcome measures in both analyses. The global OR was 1.39 (95% CI 1.071.80, p<0.02) in the treatment group in the per-protocol analysis. The benefit per 100 patients was 16.3; number needed to treat was 6.[40] Safety The NINDS rt-PA study reported that the most severe adverse event was symptomatic intracranial hemorrhage occurring within 36 hours of symptom onset in 6.4% of patients treated with alteplase versus 0.6% in those receiving placebo (p<0.001).[33] Intracranial hemorrhage was considered symptomatic if it was not previously seen on CT scan and it resulted in any decline in neurologic status. Mortality at 3 months was lower in the treatment group, but the data lacked statistical significance. In part 1, 51% of patients received intravenous alteplase within 090 minutes. In part 2, 59% also received treatment within 090 minutes, which may have contributed to enhanced safety. In addition, compliance with the inclusion and exclusion criteria along with utilization of a blood pressure algorithm was high (> 90%). This study indicated that early treatment, strict adherence to exclusion and inclusion criteria, and appropriate blood pressure management may decrease occurrence of hemorrhage.

The A0276g trial assessed efficacy and safety of intravenous alteplase in patients treated between 0 and 6 hours after onset of stroke symptoms.[35] Part A of the study was prematurely terminated due to increased hemorrhagic transformation in the 56-hour group. Treatment with alteplase significantly increased the rate of symptomatic intracerebral hemorrhage within 10 days. A confounder was noted in the baseline NIHSS scores between the placebo and treatment groups in the 56hour window analysis, where NIHSS scores of 20 or greater were noted in 23% of the treatment group compared with 8% of the placebo group (p<0.05). In the study overall, patients with an NIHSS score of 20 had an increased rate of intracranial hemorrhage and very poor outcomes. This trial demonstrated that intravenous alteplase administered 56 hours after symptom onset in patients with moderately severeto-severe strokes may cause harm. The ATLANTIS trial assessed the safety of intravenous alteplase when administered within 35 hours of symptom onset.[36] The frequency of fatal and nonfatal intracranial hemorrhage was increased in the treatment group. This trial showed that indiscriminate use of intravenous alteplase 35 hours after symptom onset may cause harm. The first ECASS trial used a higher dose of intravenous alteplase at 1.1 mg/kg (maximum 100 mg) versus 0.9 mg/kg (maximum 90 mg) in the other studies discussed, and measured safety end points of mortality and occurrence of intracranial and extracranial bleeding, with intracranial bleeding occurring within 7 days after symptom onset.[37] A higher percentage of deaths were noted in the ITT population than in the per-protocol population. A major protocol violation was treatment of patients with CT scan exclusions, which occurred in 40 (12.8%) of 313 patients. Additional protocol violations occurred in 11 patients, with seven other patients lost to follow-up, representing an additional 6%. The mortality rate among patients with major protocol violations who were randomly assigned to the alteplase group was 33.3% (20 patients) compared with 22.1% (9 patients) in the placebo group. When the per-protocol group was compared with the ITT group, the rate of hemorrhagerelated deaths decreased to 4.2% (10 patients) in the treatment group compared with 2.7% (7 patients) in the placebo group, yielding a difference that was not statistically significant (log-rank test p=0.37). This trial is important as it showed that failure to adhere to exclusion criteria such as radiographically major early infarction, hemorrhage present on CT scan, and CT scan not available or unreadable should exclude patients from receiving intravenous alteplase, and failure to do so may harm the patient. In addition, the dose of 1.1 mg/kg may not be optimal. Safety variables of the ECASS II trial included mortality at 30 and 90 days, hemorrhagic infarction, parenchymal hemorrhage, symptomatic hemorrhage, and other adverse events.[38] There was no significant difference in 30- and 90-day mortality rates between the 03-hour treatment and placebo, and the 36-hour

treatment and placebo. In the subgroup treated within 3 hours of symptom onset, there were more deaths up to day 102. In the subgroup treated 36 hours after symptom onset, 35 patients (11.3%) died by day 90. Parenchymal hemorrhage was nearly 4 times more common in the alteplase group than in the placebo group (11.8% vs 3.1%). Large, confluent, space-occupying intracranial hemorrhage (PH2) was 10 times more common in the alteplase group. The difference in the rate of PH2 hemorrhages was apparent in both time-to-treatment subgroups. The frequency of all symptomatic intracranial hemorrhage showed a 2.5-fold excess with alteplase compared with placebo. Major protocol violations numbered 34 in the alteplase group and 38 in the placebo group, mostly related to noncompliance with CT scan exclusion criteria. The Safe Implementation of Thrombolysis in StrokeInternational Stroke Thrombolysis Registry (SITS-ISTR) was an observational study that compared the safety of intravenous alteplase in 664 patients treated 34.5 hours after symptom onset with that in 11,865 patients who received treatment within 3 hours of symptom onset.[41] These data were collected and managed through a cliniciandriven Internet registry between December 2002 and November 2007. Safety outcome measures were symptomatic intracranial hemorrhage within 24 hours and mortality at 90 days. The rate of symptomatic hemorrhage, per the NINDS rtPA study definition, was 8% (52/647) in the extended-window group versus 7.3% (846/11,646) in the 03-hour window group (adjusted OR 1.13, 95% CI 0.097 1.32, p=0.11). Mortality rate at 90 days was 12.7% (70/551) in the extendedwindow group versus 12.2% (1263/10,368) in the 03-hour window group (p=0.72). However patients' baseline characteristics favored the 3.54-hour group in statistical significance for less hypertension, less hyperlipidemia, mean age 3 years younger, and NIHSS score of one point lower. This study demonstrated that an expanded time window of 34.5 hours remains safe when patients cannot be treated within the standard 3-hour time window. The SITS-MOST study was an observational study that was designed to assess the safety of alteplase within 03 hours of symptom onset in clinical practice.[39] Primary outcome measures were symptomatic deterioration in NIHSS scores (as evidenced by deterioration in NIHSS score of 4), symptomatic intracerebral hemorrhage within 24 hours, and mortality at 3 months. At 24 hours, 1.7% of patients in the treatment group (95% CI 1.42.0%) had symptomatic intracerebral hemorrhage compared with 8.5% in the randomized controlled trials. At 7 days, 7.3% in the treatment group versus 8.6% in pooled randomized controlled trials had intracerebral hemorrhage. The mortality rate at 3 months in SITS-MOST was 11.3% (95% CI 10.512.1%) compared with 17.3% (95% CI 14.121.1) in the smaller pooled randomized controlled trials. The major contribution of this study is that it shows that intravenous alteplase is as safe and effective when administered at clinical practice sites that have little previous experience with this treatment for AIS when compared with more experienced sites, such as those conducting randomized controlled stroke trials of alteplase.

European Cooperative Acute Stroke Study III

In the ECASS III trial, which studied patients who were treated with intravenous alteplase 34.5 hours after AIS, the mortality rate was 7.7% in the treatment group versus 8.4% in the placebo group (p=0.68).[6] Symptomatic intracranial hemorrhage, per the NINDS rt-PA trial definition, occurred in 7.9% of the treatment group versus 3.5% of the placebo group (p=0.006). The ECASS III trial updated the definition of symptomatic intracranial hemorrhage as any hemorrhage with neurologic deterioration combined with an NIHSS score 4 points greater than either the baseline value or the lowest value in the first 7 days, or death. In addition, the hemorrhage must have been identified as the predominant cause of the neurologic deterioration. With use of this definition, the rate of symptomatic intracranial hemorrhage was 2.4% in the treatment group versus 0.2% in the placebo group (p<0.008). Exclusion criteria differed between the NINDS rt-PA study[33] and ECASS III. Patients at an increased risk for intracranial hemorrhage with use of alteplase include those older than 75 years, NIHSS score greater than 22, major early infarct signs (mass effect, midline shift, substantial edema), and large MCA territory infarcts.[3] In the ECASS III study, patients older than 80 years, with NIHSS scores of 25 or greater, and with major ischemic infarction including large strokes as defined by one third of the MCA territory were excluded. Moreover, the median NIHSS baseline score was 9 in the ECASS III treatment group versus 14 in the NINDS rt-PA treatment group, and the maximum score in ECASS III was 24, versus 37 in NINDS rt-PA. The ECASS III trial excluded patients with diabetes and history of stroke, two independent risk factors for hemorrhagic transformation in the general AIS population, [42] whereas these patients were included in the NINDS rt-PA study. Tighter glucose level goals, safer and more effective blood pressure drugs, avoidance of plasma volume expanders, and better imaging techniques represent changes in AIS standards of care since 1995. Clinical assessments of patients, as well as management of blood pressure, oxygenation status, and heart rate, in the ECASS III trial were performed continuously, and CT or magnetic resonance imaging was performed at the discretion of the investigators in addition to at baseline and 24 hours after treatment. Admission to an intensive care unit for alteplase monitoring is now the standard of care, and many neuroscience centers provide a neurocritical care unit, all potentially contributing to better safety outcomes.[43] In addition, approximately 2.7/100 patients were harmed by the expanded time window; the number needed to harm is 35.[40] The ECASS III's major contribution to the scientific literature is safety and efficacy of intravenous alteplase in an expanded time window of up to 4.5 hours in patients with mild-to-moderate stroke. Although stricter exclusion criteria were used, the population included in the ECASS III represents a valid AIS population.

Intravenous Alteplase and Eptifibatide Combination Therapy

The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke (CLEAR) was a multicenter, double-blind, randomized, doseescalation and safety pilot study for patients with AIS who presented within 3 hours of symptom onset.[44] The CLEAR trial was the first combination trial of reduced-dose intravenous alteplase and a glycoprotein IIb-IIIa antagonist for AIS. Ninety-four patients were randomly assigned to receive either low-dose intravenous alteplase 0.3 mg/kg plus an eptifibatide 75-g/kg bolus followed by an eptifibatide 0.75-g/kg/minute infusion for 2 hours, or standard intravenous alteplase 0.9 mg/kg dosing. Once safety was established in the combination group, dose escalation of intravenous alteplase to 0.45 mg/kg plus eptifibatide was studied. The primary safety end point was symptomatic intracranial hemorrhage within 36 hours. One occurrence of symptomatic intracranial hemorrhage was noted in the combination group (69 patients) compared with two occurrences in the standard intravenous alteplase group (25 patients), which was not statistically significant (OR 0.28, 95% CI 0.061.23, p=0.09), despite a disparity of younger patients and lower NIHSS scores in the intravenous alteplaseonly group. Efficacy outcomes were similar in both groups. Because the study was doubleblinded, a design flaw may have confounded the results. The low-dose (combination) alteplase infusion group received the entire fibrinolytic over 30 minutes, whereas the standard alteplase group received two sequential infusions over 30 minutes each. Pharmacy preparation time of the multiple infusions contributed to a delay in median time to treat of 2.55 hours, whereas a median time of treatment from CT to drug was 1.35 hours. The CLEAREnhanced Regimen (ER) trial is a larger safety and efficacy trial being designed to study the combination of medium-dose alteplase plus eptifibatide.[45]

Intravenous and Intraarterial Alteplase Combination Therapy

Intraarterial fibrinolytics may be used with a mechanical clot removal device or may be used independently. The 2007 AIS guidelines added the recommendation that interventions to restore perfusion cannot be recommended outside the setting of clinical trials (class III, level B). A pilot study, the Interventional Management of Stroke Part 1 (IMS 1), used low-dose intravenous alteplase combined with intraarterial alteplase with better efficacy results and similar intracranial hemorrhage results compared with those results in the NINDS rt-PA study.[46] The Interventional Management of Stroke Part 2 (IMS 2), a second pilot study, used a similar protocol of intravenous alteplase 0.6 mg (bolus of 15% dosed over 1 min and remainder infused over 30 min) within 3 hours of symptom onset.[47] Patients

were transferred for immediate angiography, and those with a visualized occlusion received intraarterial alteplase in doses up to 22 mg within 5 hours of symptom onset with completion within 7 hours of symptom onset. The baseline median NIHSS score was 19 (inclusion criterion was a minimum NIHSS score of 10) and the median time of treatment was 142 minutes compared with 108 minutes for placebo (p<0.001). One difference between IMS 1 and IMS 2 was the utilization of the EKOS micro-infusion system (EKOS Corp., Bothell, WA), a low-energy ultrasound device that may reversibly alter the structure of the thrombus and accelerate thrombolysis. Before initiation of intraarterial therapy, an intravenous heparin 2000-unit bolus followed by an intravenous heparin infusion maintained at 450 units/hour was administered and was discontinued at completion of the intraarterial therapy. Outcome measures compared efficacy and safety of the IMS 2 trial with those in the NINDS rt-PA study[33] treatment and placebo groups. Three-month outcomes indicated an mRS score of 01 was attained in 33% of IMS 2 study patients compared with 18% in the NINDS rt-PA placebo group (OR 2.78, 95% CI 1.46 5.31) and 33% in the NINDS rt-PA treatment group (OR 1.35, 95% CI 0.72 2.56). Three-month mortality was 16% in IMS 2 versus 21% and 24% in NINDS rt-PA treatment and placebo groups, respectively; the difference was not statistically significant. The rate of symptomatic intracranial hemorrhage at 36 hours was higher in IMS 2 (9.9%) than in the NINDS rt-PA treatment group (6.6%) or placebo group (1%) and may be the result of heparin therapy during the intraarterial intervention, which was prohibited during the NINDS rt-PA study. Of the eight patients in IMS 2 with symptomatic intracranial hemorrhage, seven (88%) had an NIHSS score of 20 or greater, which is an independent risk factor for intracranial hemorrhage. Risk factors for hemorrhagic transformation are similar between intravenous and intraarterial administration, with higher NIHSS scores, longer time to recanalization, lower platelet count, and higher blood glucose levels as independent predictors of hemorrhagic transformation.[48] The Interventional Management of Stroke Part 3 (IMS 3) is an ongoing head-tohead trial to determine whether a combined intravenous-intraarterial approach to recanalization is superior to standard intravenous alteplase alone when treatment is started within 3 hours of stroke symptom onset.[49] As of this writing, 320 patients had been enrolled in 59 sites internationally.

Monitoring of Intravenous Alteplase Therapy

The pharmacokinetic and pharmacodynamic properties of alteplase must be examined and understood by the entire health care team. The clinician should be made aware that the administration of antithrombotics and anticoagulants is contraindicated for 24 hours after administration of intravenous alteplase. Close monitoring of the patient in a neurology or similar intensive care unit, with personnel trained in recognizing acute neurologic changes, is vital. Bleeding precautions should be taken, along with strict neurologic and blood pressure

monitoring. Although specific monitoring parameters for blood pressure and neurologic assessments can be found in the literature, a comprehensive monitoring plan is lacking. For this reason, we present a more comprehensive monitoring plan used at our primary stroke center (Figure 2). Patients with AIS should remain at bed rest, and any activity that might contribute to the patient falling must be avoided. A plan to identify and treat symptomatic hemorrhagic transformation must be in place to handle neurologic emergencies. Agents needed for treatment must be preidentified and made easily available. Any abrupt decrease in neurologic function including loss of consciousness or sudden severe headache, nausea, and vomiting may be symptoms of a hemorrhagic transformation.

Figure 2. Sample of the form used at Baptist Medical Center (Jacksonville, FL) for their comprehensive monitoring plan when administering intravenous alteplase to patients with stroke.

Guideline recommendations for control of intracranial bleeding from fibrinolytic therapy include the infusion of platelets 68 units and cryoprecipitate that contains factor VIII to rapidly correct the fibrinolytic state.[50] It is recommended that 10 units of cryoprecipitate be administered rapidly because cryoprecipitate contains fibrinogen, the most specific reversal agent for fibrinolytics.[51] To obtain cryoprecipitate, a type and screen is necessary. Neurosurgical evacuation may be warranted.

Mechanical Thrombectomy and Fibrinolytics

In 2007, the AIS stroke guidelines recognized the Merci Retriever (Concentric Medical, Mountain View, CA) as a mechanical thrombectomy device with benefits in carefully selected patients with AIS.[3] Because recanalization is less likely after intravenous alteplase in patients with large-vessel AIS as a consequence of large-clot burdens, thrombectomy offers an alternative method of recanalization in this population.[3, 52] In addition, this approach may be more desirable in patients ineligible to undergo fibrinolysis because of recent surgery. However, this intervention must be performed in a catheterization laboratory by experienced radiologists skilled in neuroendovascular techniques. The Multi Mechanical Embolus Removal in Cerebral Ischemia (Multi MERCI) trial was an international, multicenter, prospective, single-arm trial of thrombectomy within 8 hours of symptom onset in patients with large-vessel occlusion.[53] The primary outcome measure was recanalization of the target vessel. Of the 164 patients enrolled, all patients received mechanical thrombectomy with use of the most recent version of the Merci Retriever system and also received intraarterial alteplase up to 24 mg if needed. Patients with largevessel disease in whom recanalization failed after receiving intravenous alteplase within 3 hours of symptom onset were included. Baseline demographics included mean SD age of 68.1 16.0 years, median NIHSS score of 19 (range 1523), and mRS scores of 0 (86% of patients), 1 or 2 (6%), 3 (5%), or 4 (3%). Mean time from symptom onset to arterial puncture was 3.9 hours in the intravenous alteplase group compared with 4.6 hours in the nonintravenous alteplase group (p<0.031) and 3.7 hours in the intraarterial alteplase group compared with 4.8 hours in the nonintraarterial alteplase group (p<0.001). Nineteen protocol violations related to the mechanical intervention were noted. Ten patients required snares or other foreign body retrievers and nine required balloon angioplasty at the thrombus site. Eleven patients received intraarterial glycoprotein IIb-IIIa antagonists and 10 required stent placement before thrombectomy. At the end of the study, 68% of patients (95% CI 6175%) had undergone successful recanalization. Forty-eight patients (29.3%) received intravenous

alteplase before angiography and showed similar efficacy in final recanalization rates with those who did not receive intravenous alteplase (73% vs 66%, p=0.46). Of these, 35% received additional intraarterial alteplase. At 90 days, 36% achieved a favorable neurologic outcome (mRS score 02). The intracranial hemorrhage rate in those who received any alteplase and device compared with those who received device alone was 11% versus 7.9% (p=0.60). Rates of symptomatic intracranial hemorrhage and symptomatic parenchymal hematoma type 2 (defined as a dense hematoma greater than 30% of the infracted area with substantial space-occupying effect or any hemorrhagic lesion outside the infarcted lesion)[54] were reported. Rates were similar between patients who received intravenous alteplase and those who did not (10% vs 9.5%, p=0.99) and (2.1% vs 2.6%, p=0.99), respectively. Rates of symptomatic intracranial hemorrhage and parenchymal hematoma type 2 were higher in the intraarterial group than in the nonintraarterial group (14% vs 7.5%, p=0.27) and (3.5% vs 1.9%, p=0.61), respectively); although, the differences were not statistically significant. A 34% overall mortality rate was noted. Fifty-two patients (32%) failed recanalization, and the 90-day mortality rate among this group was 52% (95% CI 3866%) compared with 25% (95% CI 1733%) in patients for whom recanalization was successful; the absolute difference in mortality was 27%. Patients in this trial had severe baseline neurologic deficits as evidenced by a median NIHSS score of 19, an independent risk factor for mortality. This trial established the importance of recanalization in decreasing mortality rates in patients with large-vessel disease. A recently approved device call the Penumbra System (Penumbra, Inc., Alameda, CA) was designed to evacuate a clot with placement of a clot disrupter centrally into the clot. Unlike the Merci Retriever, the Penumbra device also uses an applied vacuum to remove the macerated thrombus.[55]

Urgent Carotid Endarterectomy

Urgent carotid endarterectomy generally is not performed in patients with AIS because the sudden restoration of blood flow may increase the development of brain edema or lead to hemorrhagic transformation, especially among patients with major infarctions.[3] A recently published systematic review of studies published between 1980 and 2008 reported the pooled absolute risk of stroke or death after urgent carotid endarterectomy was 20.2% (95% CI 12.028.4%) and was greater than that in patients with stable disease who undergo carotid endarterectomy (OR 1.2, 95% CI 0.91.6, p=0.13).[10]

Intracranial Stent Placement

Until recently, intracranial stent placement was limited to off-label use of balloonmounted stents designed for cardiac circulation.[11] Because these stents are rigid, they are poor tools for treating intracranial disease because of weak navigational ability in the tortuous intracranial circulation.[11] A new generation of selfexpanding intracranial stents as an option for patients refractory to conventional AIS management offers new alternatives for intracranial stent placement. The Wingspan self-expanding intracranial stent (Boston Scientific, Natick, MA) has demonstrated technical feasibility with high rates of recanalization. [11] Optimal long-term safety strategies to limit in-stent thrombosis must be determined before large clinical trials can be designed since subacute stent thrombosis has occurred in patients with standardized antiplatelet therapy.[56]

The Heparin Controversy

The heparin controversy revolves around studies in which heparin was used inappropriately (albeit retrospectively) and resulted in poor outcomes. A consensus among stroke management providers is that the efficacy of intravenous unfractionated heparin (UFH) has been inadequately tested in patients with defined stroke subtypes and occlusive vascular lesions.[57] In the presence of contraindications to clot removal, UFH may be useful in the treatment of AIS in patients with specific stoke subtypes. These subtypes include cerebral venous thrombosis, large-artery occlusions with a critical stenosis, or cardiac sources of emboli. Unfractionated heparin may be used as a bridge to full therapeutic anticoagulation with warfarin when warfarin is indicated.[58, 59] The current AIS guidelines recommend against the use of heparin in patients with AIS regardless of the underlying issue (class III, level A), whereas the American College of Chest Physicians guidelines recommend UFH for patients with AIS of cardioembolic sources.[3, 60] When UFH is used in patients with AIS, blood pressure must be managed appropriately to reduce the risk of hemorrhagic transformation. Monitoring for heparin toxicity should include platelet counts for early identification of heparin-induced thrombocytopenia. One thing remains consistent between the guidelines and stroke management providers: there is no role for therapeutic dosing of low-molecular-weight heparin (LMWH) in the treatment of AIS.[3] A meta-analysis evaluated safety and efficacy data from 10 randomized controlled trials of LMWHs in patients with AIS.[61] Although LMWHs reduced venous thromboembolic events in patients with AIS, the risk of extracranial bleeding did not outweigh the reduction in death or disability. Therefore, the consensus among stroke management providers is that LMWH has no role in the treatment of AIS, but it may be used along with heparin to prevent deep vein thrombosis.[3]

Antithrombotic Agents

Aspirin 325 mg/day should begin within 2448 hours of AIS therapy and is the only anti-thrombotic to receive a class I, level A rating.[3] Because previous stroke is a risk factor for another AIS event, patients may be taking aspirin, clopidogrel, or extended-release dipyridamoleaspirin at presentation. Although these agents should not be given within 24 hours of intravenous alteplase, their previous use does not preclude administration of intravenous alteplase. The standard of care is to determine compliance with the presenting agent, and if the patient is compliant, a change to another agent may be considered or alternatively the addition of lowdose aspirin to clopidogrel may be considered for breakthrough therapy.

Maintenance of Euglycemia
Hyperglycemia has been associated with poor outcomes, and an increase in blood glucose level is an indicator of a more serious stroke. It may affect the blood-brain barrier, causing brain edema and possible hemorrhagic transformation.[62] In 728 patients both diabetic and nondiabetic from the ECASS II trial, glucose levels were measured at baseline and at 24 hours.[63] Results showed that nondiabetic baseline hyperglycemia was not associated with worsening outcomes, but persistent hyperglycemia was associated with adverse events. In patients with diabetes, hyperglycemia was not related to stroke outcomes. The recently published Normoglycemia in Intensive Care EvaluationSurvival Using Glucose Algorithm Regulation (NICE-SUGAR) trial evaluated intensive lowering of blood glucose level (range 81108 mg/dl) compared with conventional lowering (< 180 mg/dl) in critically ill patients.[64] The intensive group showed deleterious outcomes in critically ill patients, whereas a lower mortality was linked to the conventional group. A meta-analysis of five randomized controlled trials revealed that although intensive control of hyperglycemia decreases cardiovascular events, it does not have an effect on all-cause mortality.[65] Controversy still exists as to which patients should receive intensive control as well as the appropriate goal level for blood glucose. Concerns of the patient developing hypoglycemia are valid and should be addressed with frequent monitoring of blood glucose levels.

Blood Pressure Management

Assessment and management of blood pressure during AIS are critical. Many patients experiencing stroke will have a natural decline in blood pressure during the first 24 hours after the event and may become hemodynamically unstable, a negative prognostic risk factor.[66, 67] The causes of hypotension must be evaluated and treated. Treatment for hypovolemia includes volume replacement with normal saline.[3] Vasopressor support with dopamine may be used.[3] Often, patients with acute strokes will have an increase in blood pressure, which may represent a compensatory mechanism to maintain cerebral blood flow. Other causes of hypertension include pain, nausea, acute stress due to the event, increased bladder pressure, and increased intracranial pressure.[67] Pain control with nonsedating drugs such as topical anesthetic patches or ice packs to localized

areas of pain may be preferred in order to avoid sedation and interference with neurologic assessment. Blood pressure goal setting must be individualized to the patient. Patients receiving intravenous alteplase require a systolic blood pressure less than 185 mm Hg and diastolic blood pressure less than 110 mm Hg to avoid hemorrhagic transformation.[3] For patients not receiving fibrinolysis, a reduction in blood pressure should be avoided to prevent a decrease in cerebral blood flow and cerebral perfusion pressure, which may expand the infarct and cause harm. Because long-standing hypertension upregulates the cerebral perfusion pressure oxygenation curve, high blood pressure at presentation should not be treated unless a compelling reason exists such as concurrent myocardial infarct, hemorrhagic transformation, or other end-organ damage.[67] Furthermore, abrupt reductions in blood pressure must be avoided. Blood pressure agents of choice are those that are easily titratable and have safe and predictable results.[3] First-line therapies include nicardipine and labetalol.[3] Nicardipine's advantage is easy dose titration and predictability. It can be rapidly titrated, and after discontinuation the blood pressure returns to baseline. Labetalol's advantages include its low cost and -blockade in patients with atrial fibrillation; it represents a rational first-line agent for patients who cannot take oral agents and those who have been taking blockers before the event, thereby avoiding abrupt withdrawal of the drug. Each patient's comorbidities and current drug therapies should be assessed before deciding on an appropriate agent. Nitroprusside is now considered a third-line agent because of its undesirable safety profile, as it may contribute to increased intracranial pressure and cyanide toxicity.[3] The Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS) trial is a recently completed randomized, double-blind, placebocontrolled trial that evaluated treatment of blood pressure in patients with AIS or intracranial hemorrhage within 36 hours of symptom onset.[68] Patients with intracranial hemorrhage were excluded if they had systolic blood pressure of 200 mm Hg or more, or diastolic blood pressure of 120 mm Hg or more. Blood pressure goals were 145155 mm Hg or a reduction of 15 mm Hg over baseline. Patients who received intravenous alteplase were excluded. Intravenous or oral labetalol 50 mg/day, oral or sublingual lisinopril 5 mg/day, or a combination of both were compared with placebo in patients with systolic blood pressure greater than 160 mm Hg; oral preparations were used in the absence of dysphasia. Patients who did not reach goal blood pressure after 8 hours of initial treatment received an additional treatment dose. Scheduled dosing began 24 hours after the initial dose. The mean time to treatment was 19.2 hours in the labetalol group, 20.5 hours in the lisinopril group, 19.8 hours in the combination group, and 17.6 hours in the placebo group. The primary end point was death or dependency (mRS score 4) at 2 weeks. The secondary end points included identification of early neurologic

deterioration (increase of NIHSS scores of 4 points) at 72 hours and a comparison of different treatment regimens in reaching blood pressure goals. No significant differences in death or dependence at 2 weeks were noted among the groups, with the relative risk of active treatment versus placebo of 1.03 (95% CI 0.801.33, p=0.83). No evidence of early neurologic deterioration within the active treatment group was noted despite a significantly greater decrease in systolic blood pressure of 21 mm Hg (1725 mm Hg) and diastolic blood pressure of 11 mm Hg (517 mm Hg, p=0.004) within the first 24 hours of symptom onset. More severe adverse events were seen in patients with dysphasia in the placebo group and the least in the oral labetalol group. Treatment was discontinued in 18 patients due to serious adverse events: six in the labetalol group, eight in the lisinopril group, and four in the placebo group; however, a casual relationship was inferred between the study drugs for only two patients in the labetalol group and two in the lisinopril group. One case of bronchospasm in each of the labetalol and lisinopril groups required nebulized bronchodilators; one patient in the labetalol intracranial hemorrhage group had extension of the infarct and one patient in the lisinopril group experienced hypotension. After 2 weeks, a statistically significant difference from baseline in systolic blood pressure was noted only in the combination group when compared with placebo; mean difference in systolic blood pressure was 10 mm Hg (95% CI 317 mm Hg, p=0.004). The trial was small (179 patients), and larger trials are needed to support these findings.

Neuroprotectants
Many neuroprotective drugs for AIS have appeared to work in animals but fail when tested in humans.[69] The mechanism of action of neuroprotectants typically targets direct or indirect antagonism of glutamate, a known neurotoxic central nervous system transmitter. Indirect mechanisms include antagonism of Nmethyl-D-aspartic acid (NMDA), a glutamate mimetic at the NMDA receptor, or inhibition of nitric oxide, a known stimulant of glutamatemediated processes. Once glutamate-mediated processes are started, highly toxic peroxynitrate free radicals are formed, causing brain cell apoptosis. Many neuroprotective therapies are being studied in patients with AIS. In addition to hypothermia, intravenous magnesium has shown promise.[70] Statins and cerebral edema containment are also being evaluated. Statins The benefit of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in patients with AIS may be independent of lowering the levels of lowdensity lipoprotein cholesterol. Pleiotropic effects include plaque stabilization and

antiinflammatory effects; a review of the pleiotropic effects of statins is outside the scope of this article. The Northern Manhattan Observational Stroke Study (NOMAS) was a population-based study that identified a decline in clinical worsening in patients admitted for AIS to a large university medical center who were taking statins at presentation compared with those not taking a statin (5.3% vs 12.2%, p=0.04).[71] In addition, 90-day mortality was reduced in the statin group (1.8% vs 10.6%, p=0.03). The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial established the role of high-dose stains in secondary prevention; the Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART II) is a safety study evaluating shortterm, high-dose lovastatin use in patients with AIS.[72, 73] The pleiotropic effects of statins as a class effect and optimal dosing strategies remain unanswered and are being studied in clinical trials. Statin withdrawal in patients with AIS should be avoided.[74] Magnesium Magnesium blocks calcium-mediated glutamine reuptake into neuronal axons. The Field Administration of Stroke TherapyMagnesium (FAST-MAG) openlabel, single-arm pilot study allowed paramedics to administer intravenous magnesium 2.5 g in the field to patients with probable stroke followed by an additional 1.5-g bolus and maintenance infusion of 16 g delivered over 24 hours.[70] Patients were followed for 90 days. Although the trial had a small sample (20 patients), results indicated improvement in 20%, deterioration in 7%, and no change in 73% of patients receiving intravenous magnesium. At 3 months, 69% of patients had good functional outcomes, whereas 20% died. A large phase III clinical trial, the goal of which is to evaluate the effectiveness and safety of field-initiated magnesium sulfate in improving the long-term functional outcome of patients with acute stroke, is under way.[75] Hypothermia Induced hypothermia is one of the most promising neuroprotective therapies in AIS because increased body temperature has been associated with poor stroke outcomes.[9, 76] Patients with AIS most likely to benefit from this therapy include those with moderate-to-severe stroke and those with large-vessel occlusions and cerebral edema.[77] Also, elevated body temperatures immediately after stroke predict poor outcomes; therefore, controlling fever with acetaminophen and temperature-controlling devices should be a priority. A decreased body temperature to hypothermic levels of 3236C has proved neuroprotective in both humans and animal models.[77] Hypothermia slows metabolic demands on the body, decreases calcium influx into cells, and suppresses the production of free radicals. Such methods have been proved useful in patients with cardiac arrest at presentation; therefore, the same principles may

be applied to patients with stroke.[78] The 2007 guidelines recommend induced hypothermia in patients with AIS as a class III, level B recommendation.[3] Cooling can be divided into three distinct phases: induction, maintenance, and rewarming. Based on the available literature, temperature control should ideally start within 412 hours after symptom onset, and cooling should progress as rapidly as possible.[9] Care should be taken not to decrease body temperature below the target when inducing and maintaining temperatures. The appropriate duration of hypothermia has not been established, and the number of patients treated with hypothermia in controlled trials is small. However, one trial maintained patients at an average of 32C for 48 hours (range 1272 hrs) with safe and effective outcomes.[77] Another study investigated hypothermia at 12 hours and 24 hours and found no significant difference in outcome.[79] Methods of achieving hypothermia vary, but essentially they are either extravascular (topical) or endovascular. Extravascular methods include cooling blankets, ice baths and ice lavage, and conductive cooling-rewarming machines that supply continuous temperature-controlled water flow externally. Endovascular methods encompass the administration of chilled intravenous solutions often through a catheter placed into the central venous system usually by femoral, subclavian, or internal jugular access.[80] Multiple devices exist for both extravascular and endovascular cooling. Clinicians should also be aware of potential adverse effects of therapeutic hypothermia including hypotension, infection, and cardiac arrhythmias. One of the most important measures to implement when inducing a hypothermic state is to sedate the patient because this will cause vasodilation and further facilitate heat loss through surface cooling.[9, 81] Monitoring parameters during cooling include continuous blood pressure and cardiac monitoring.[80] Hypothermia-induced bradycardia and hypokalemia may manifest when inducing hypothermic states.[9] Skin lesions, although rare, may be due to excessive exposure to cooling-device surfaces.[9] A secondary temperature gauge in addition to the primary temperature gauge on the cooling device, such as a urinary bladder probe (only effective when the patient has adequate urinary output), a pulmonary artery probe, or rectal probe, may be used to adequately assess internal temperatures.[9] Patients are at a greater risk for developing bacterial infections because inflammatory response is suppressed by cooling longer than 24 hours.[9] One major adverse effect of hypothermia is shivering, the body's natural way of warming.[9] Shivering expends energy and warms the body, both of which are undesirable during induced hypothermia. A number of countermeasures have been used to lower the shivering threshold such as warming the hands, feet, and face in addition to drugs such as buspirone, meperidine, magnesium, and neuromuscular blockade.[82] Neuromuscular blockade requires both mechanical ventilation and pain management and sedation.

Caution should be used when rewarming techniques are started. Monitoring parameters include continuous blood pressure and cardiac monitoring.[9] Rapid rewarming may produce rebound hypotension; therefore, a patient should not be rewarmed faster than a rate of 0.05C/hour, and the warming process should take approximately 812 hours.[9] Rewarming must be slow and controlled to prevent adverse effects such as hypotension and hyperkalemia.[9, 83] Containment of Cerebral Edema Malignant MCA occlusions represent 10% of all AIS cases.[84] Although most other patients with AIS will develop some cytotoxic edema, most will not develop high intracranial pressure as a consequence. Early-onset cytotoxic and vasogenic edema with sustained intracranial pressures greater than 20 mm Hg (normal is 5 15 mm Hg) may lead to permanent neurologic damage, brain herniation, or death. Mortality rates of up to 80% have been reported in this stroke subtype.[85] When cytotoxic edema develops during a malignant MCA occlusion, it is within minutes to hours and does not respond to dexamethasone. Cytotoxic edema primarily reflects failure of the membrane sodium- and potassium-activated adenosine triphosphatase pump due to tissue ischemia and leads to early intracellular sodium, chloride, and calcium accumulation.[86] The calcium and other stimuli trigger lipolysis, proteolysis, nitric oxide production, endonucleasemediated DNA degradation, and the activation of kinases and phosphatases.[86] These alter protein function and initiate upregulation of multiple genes. Such immediate early genes include those encoding transcription factors, heat shock proteins, cytokines, chemokines, and adhesion molecules.[86] Vasogenic edema is characterized by progressive loss of blood-brain barrier integrity with extravasation of water, intravascular proteins, and inflammatory cells. Dexamethasone does have a role in vasogenic edema in brain hemorrhage, although its role is less clearly defined. Development of vasogenic edema tends to cause greater clinically significant space-occupying edema.[86] Treatment of this subtype is aimed at containment of cerebral edema and includes decompressive hemicraniectomy, which is the surgical removal of part of the skull to accommodate the swollen brain. The current 2007 AIS guidelines list hemicraniectomy as class IIa, level B,[3] but it has since gained popularity due to three recently published European randomized trials.[84, 85, 87] All three trials were stopped early due to improved outcomes in the hemicraniectomy group versus those receiving traditional medical management. Additional interventions are aimed at the management of intracranial pressure and are beyond the scope of this article.[88]

Ongoing Trials

Tirofiban, argatroban, desmoteplase, and tenecteplase are drugs currently being studied for the treatment of AIS.[89] Ongoing neuroprotective studies include those evaluating magnesium, minocycline, citicoline, and hypothermia.[89] Historically, AIS research has yielded little progress and lagged behind research in cardiac and other cardiovascular diseases. Collaboration within the AIS community has increased over the years. Two such collaborative practices include the Stroke Therapy Academic Industry Roundtable (STAIR)[90] and the Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) consortium.[91] The STAIR consortium brings together neurologists, other physicians, industry representatives, and regulators to discuss issues related to the development of new AIS therapies.[90] They recently recommended that clinical trials should focus on selected patient populations most likely to respond to investigational therapies. Additional recommendations include that penumbral imaging be incorporated into trials and that patients enrolled in investigational trials have rescue therapy options available when needed. The National Institutes of Health (NIH) has been instrumental in the support of stroke studies and collaborative practices. The SPOTRIAS is an NIH-supported collaborative practice of eight centers that share resources and data to facilitate translation of basic research findings into clinical practice.[91] The development of specialized research resources, improved research model systems, and expansion of the research base through collaboration nationwide are methods to reaching the goal of reducing disability and mortality in patients with AIS.

Conclusion
As treatment interventions become more clearly defined in special subgroups of patients, outcomes in AIS will likely continue to improve. The heterogeneity of AIS has made targeted therapies more elusive. The past few years has yielded a plethora of new information relating to treatment of large-vessel disease and severe stroke, the role of biomarkers, infection and inflammation, thrombectomy, and intracranial stent placement. Intravenous alteplase has been the mainstay of AIS treatment since 1995, but the 3-hour time window between symptom onset and drug administration was often missed and patients were excluded. The landmark trial, ECASS III, identified patients with mild-tomoderate AIS who may safely receive intravenous alteplase up to 4.5 hours after symptom onset; this finding will enable many more patients to receive the drug. In addition, new devices for thrombolectomy are being developed, and neuroprotective therapies such as the use of magnesium, statins, and induced hypothermia are being explored. References

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