Acute Stroke Management

Background

Stroke is the clinical term for acute loss of perfusion to vascular territory of the brain, resulting in ischemia and a corresponding loss of neurologic function. Classified as either hemorrhagic or ischemic, strokes typically manifest with the sudden onset of focal neurologic deficits, such as weakness, sensory deficit, or difficulties with language. Ischemic strokes have a heterogeneous group of causes, including thrombosis, embolism, and hypoperfusion, whereas hemorrhagic strokes can be either intraparenchymal or subarachnoid.

Only in recent years have advances been made that enable physicians to significantly improve the outcome of this devastating disease. A new era in acute stroke care began in 1995, when the National Institute of Neurologic Disorders and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Study Group first presented data indicating that early administration of t-PA benefited a carefully selected patient group with acute ischemic stroke (AIS). Currently, t-PA is the only approved therapy for AIS, and despite proven efficacy, utilization rates of rt-PA remain low.

Pathophysiology

The brain is the most metabolically active organ in the body. While representing only 2% of the body's mass, it requires 15-20% of the total resting cardiac output to provide the necessary glucose and oxygen for its metabolism. Ischemic strokes result from events that limit or stop blood flow, such as embolism, thrombosis in situ, or relative hypoperfusion. As blood flow decreases, neurons cease functioning, and irreversible neuronal ischemia and injury begin at blood flow rates of less than 18 mL/100 mg/min.

Ischemic cascade

The processes involved in stroke injury at the cellular level are referred to as the ischemic cascade. Many factors are thought to result in cell death and dysfunction, and others are being discovered at a rapid rate. Within seconds to minutes of the loss of glucose and oxygen delivery to neurons, the cellular ischemic cascade begins. This is a complex process that begins with cessation of the normal electrophysiologic function of the cells. The resultant neuronal and glial injury produces edema in the ensuing hours to days after stroke, causing further injury to the surrounding tissues.

Ischemic penumbra

An acute vascular occlusion produces heterogeneous regions of ischemia in the dependent vascular territory. The quantity of local blood flow is comprised of any residual flow in the major arterial source and the collateral supply, if any. Regions of the brain without significant flow are referred to collectively as the core, and these cells are presumed to die within minutes of stroke onset. Zones of decreased or marginal perfusion are collectively called the ischemic penumbra. Tissue in the penumbra can remain viable for several hours because of marginal tissue perfusion, and currently studied pharmacologic interventions for preservation of neuronal tissue target this penumbra.

Administration of t-PA to the patient with an acute stroke attempts to establish revascularization so that cells in the penumbra can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly. Neuroprotective strategies are intended to preserve the penumbral tissues and extend the time window for revascularization techniques. While none to date have shown broad benefit in clinical trials, several trials are underway.

Mechanisms of stroke

Embolic strokes

Emboli may either be of cardiac or arterial origin. Cardiac sources include atrial fibrillation, recent myocardial infarction, prosthetic valves, native valvular disease, endocarditis, mural thrombi, dilated cardiomyopathy, or patent foramen ovale allowing passage of venous circulation emboli. Arterial sources are atherothrombolic or cholesterol emboli that develop in the arch of the aorta and in the extracranial arteries (ie, carotid and vertebral arteries). Embolic strokes tend to have a sudden onset, and neuroimaging may demonstrate previous infarcts in several vascular territories or calcific emboli.

Thrombotic strokes

Thrombotic strokes include large-vessel strokes and small-vessel or lacunar strokes. They are due to in situ occlusions on atherosclerotic lesions in the carotid, vertebrobasilar, and cerebral arteries, typically proximal to major branches. Thrombogenic factors may include injury to and loss of endothelial cells exposing the subendothelium and platelet activation by the subendothelium, activation of the clotting cascade, inhibition of fibrinolysis, and blood stasis. Thrombotic strokes are generally thought to originate on ruptured atherosclerotic plaques. Intracranial atherosclerosis may be the cause in patients with widespread atherosclerosis. In other patients, especially younger patients, other causes should be considered, including hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S deficiency), sickle cell disease, fibromuscular dysplasia, arterial dissections, and vasoconstriction associated with substance abuse.

Lacunar stroke

Lacunar strokes represent 20% of all ischemic strokes. They occur when the penetrating branches of the middle cerebral artery (MCA), the lenticulostriate arteries, or the penetrating branches of the circle of Willis, vertebral artery, or basilar artery become occluded. Causes of lacunar infarcts include microatheroma, lipohyalinosis, fibrinoid necrosis secondary to hypertension or vasculitis, hyaline arteriosclerosis, and amyloid angiopathy. The great majority are related to hypertension.

Watershed infarcts

These infarcts, also known as border zone infarcts, develop from relative hypoperfusion in the most distal arterial territories and can produce bilateral symptoms. Frequently, these occur perioperatively or in situations of prolonged hypotension.

Frequency

United States

Approximately 705,000 strokes occur each year, including both new and recurrent cases. Of these strokes, approximately 625,000 are ischemic strokes. By the year 2025, the annual number of strokes is expected to reach 1 million. Currently, more than 4.4 million people in the United States are stroke survivors.

International

As in the United States, stroke is the third leading cause of death in the industrialized countries of Europe and the leading cause of adult disability. The global incidence of stroke will only increase, since the population older than 65 years will rise from 390 million now to 800 million by 2025, representing 10% of the total population.

Mortality/Morbidity

• Stroke is the third leading cause of death in the United States (60.2 per 100,000), following cardiac and cancer-related deaths. Approximately 29% of patients die within 1 year following a stroke; this percentage rises in patients older than 65 years. Worldwide in 1990, more than 4.3 million people died of cerebrovascular disorders.
• Stroke is the leading cause of disability in the United States; 31% of stroke survivors assistance with daily living, 20% need some type of assistance for walking, and 16% require admission to a long-term care facility. Furthermore, at least one third of stroke survivors have depression as well as many of their care providers.

• The direct costs (ie, treatment) and indirect costs (ie, lost productivity) of stroke in the United States are approximately $43 billion/year.

Race

In the United States, stroke has a higher incidence in the black population than in the white population.

• In black males, the incidence is approximately 93 per 100,000, with a death rate of approximately 51%. In black females, incidence is 79 per 100,000 with a death rate of 39.2%. Young blacks have a 2-5 times greater risk of ischemic stroke than the white population of the same age, and they are 2.5 times more likely to die of stroke. Blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites.

• White males have a stroke incidence of 62.8 per 100,000, with death being the final outcome in 26.3% of cases, compared with women who have a stroke incidence of 59 per 100,000 and a death rate of 39.2%.

• Hispanics have a lower overall incidence of stroke than whites and blacks but more frequent lacunar strokes and stroke at an earlier age.

Sex

In patients younger than 60 years, the incidence of stroke is greater in males (3:2 ratio).

Age

• Stroke can occur in patients of all ages, including children.

• Risk of stroke increases with age, especially in patients older than 64 years, in whom 75% of all strokes occur.

Treatment

Medical Care

Medical care for AIS occurs on a continuum, beginning in the prehospital setting and ending at home after discharge. Stroke centers and organized protocols for the acute and in-house treatment of stroke patients have been shown to decrease morbidity and mortality associated with stroke.

• Prehospital care personnel are critical elements in the AIS chain of survival. Emergency medical services (EMS) personnel should begin with the ABCs and, once the patient's condition is stable, should perform a more directed assessment and administer supportive treatment.
  
  
  • Prehospital stroke assessment tools, such as the Cincinnati Prehospital Stroke Scale or Los Angeles Prehospital Stroke Scale, identify patients with potential stroke. Providing supplemental oxygen when indicated, establishing intravenous lines, measuring serum glucose, and administering glucose in hypoglycemic patients are elements of prehospital stroke care.
  
  
  • Equally important is prehospital triage and notification of a potential stroke patient. This allows for early mobilization of necessary resources, such as a stroke team, radiology, and pharmacy.
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  • With the creation and certification of primary stroke centers, regional health care systems should determine the best triage policy for potential stroke patients in their area.
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• The goal of acute stroke management in the emergency department is rapid and efficient care. Continuing from the assessment of the ABCs, stroke patient evaluation and, if eligible, fibrinolytic therapy should be administered within 1 hour from presentation as shown below.

  Table 2. NINDS Recommended Stroke Evaluation Time Benchmarks for Potential Thrombolysis Candidate
  

• Time Interval	Time Target
  Door to doctor Access to neurologic expertise Door to CT scan completion Door to CT scan interpretation Door to treatment Admission to monitored bed	10 min 15 min 25 min 45 min 60 min 3 h

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• Again, general stroke management is a team effort with the nursing and medical staff working closely together. General stroke care issues are outlined in the table below.

  Table 3. General Management of Patients With Acute Stroke

  Blood glucose	Treat hypoglycemia with D50 Treat hyperglycemia with insulin if serum glucose >200 mg/dL
  Blood pressure	See recommendations for thrombolysis candidates and noncandidates.
  Cardiac monitor	Continuous monitoring for ischemic changes or atrial fibrillation
  Intravenous fluids	Avoid D5W and excessive fluid administration IV isotonic sodium chloride solution at 50 mL/h unless otherwise indicated
  Oral intake	NPO initially; aspiration risk is great, avoid oral intake until swallowing assessed
  Oxygen	Supplement if indicated (Sa02 <90%,>
  Temperature	Avoid hyperthermia, oral or rectal acetaminophen as needed

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• Hypoglycemia and hyperglycemia need to be identified and treated early in the evaluation. Not only can both produce symptoms that mimic ischemic stroke, but both also can aggravate ongoing neuronal ischemia. Administration of glucose in hypoglycemia produces profound and prompt improvement, while insulin should be started for patients with stroke and hyperglycemia. Ongoing studies will help determine the optimal level of glycemic control.
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• Hyperthermia is infrequently associated with stroke but can increase morbidity. Administration of acetaminophen, by mouth or per rectum, is indicated in the presence of fever (temperature >100.4°F).


• Supplemental oxygen is recommended when the patient has a documented oxygen requirement. To date, conflicting evidence exists that supernormal oxygenation improves outcome.
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• Optimal blood pressure targets remain to be determined. Many patients are hypertensive on arrival. Recent American Stroke Association guidelines have reinforced the need for caution in lowering blood pressures acutely. Table 4 shows current recommendations for both candidates and noncandidates for thrombolytic therapy.
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• In the small proportion of patients with stroke who are relatively hypotensive, pharmacologically increasing blood pressure may improve flow through critical stenoses.

  Table 4. Blood Pressure Management in Patients With Stroke*
  

  	Blood Pressure	Treatment
  Candidates for fibrinolysis	Pretreatment SBP >185 or DBP >110 mm Hg	Labetalol 10-20 mg IVP 1-2 doses or Enalapril 1.25 mg IVP
  	Posttreatment DBP >140 mm Hg SBP >230 mm Hg or DBP 121-140 mm Hg SBP 180-230 mm Hg or DBP 105-120 mm Hg	Sodium nitroprusside (0.5 mcg/kg/min) Labetalol 10-20 mg IVP and consider labetalol infusion at 1-2 mg/min or nicardipine 5 mg/h IV infusion and titrate Labetalol 10 mg IVP, may repeat and double every 10 min up to maximum dose of 150 mg
  Noncandidates for fibrinolysis	DBP >140 mm Hg SBP >220 or DBP 121-140 mm Hg or MAP >130 mm Hg SBP <220 mm Hg or DBP 105-120 mm Hg or MAP <130>	Sodium nitroprusside 0.5 mcg/kg/min; may reduce approximately 10-20% Labetalol 10-20 mg IVP over 1-2 min; may repeat and double every 10 min up to maximum dose of 150 mg or nicardipine 5 mg/h IV infusion and titrate Antihypertensive therapy indicated only if AMI, aortic dissection, severe CHF, or hypertensive encephalopathy present

  *Adopted from 2005 Advanced Cardiac Life Support (ACLS) guidelines and 2003 American Stroke Association Scientific Statement
  Abbreviations: SBP - systolic blood pressure; DBP - diastolic blood pressure; IVP - intravenous push; MAP - mean arterial pressure

• Fibrinolytic therapy: Intravenous t-PA for appropriate patients within 3 hours from symptom onset remains a Class I recommendation by the American Stroke Association. A recent re-analysis of the original NINDS data reaffirmed the original findings. Similarly, a meta-analysis of published t-PA use demonstrated efficacy and safety comparable to that of the original NINDS trial.

Surgical Care

Surgical intervention is rarely required urgently in AIS; however, current recommendations suggest that neurosurgical care should be available within 2 hours when needed, eg, to evaluate surgical options in hemorrhagic transformation following t-PA or in the management of life-threatening elevations of ICP.

• Increased ICP is a life-threatening event occurring in as many as 20% of all strokes; it is more common in large, hemispheric strokes. Edema and herniation are the most common causes of early death in patients with hemispheric stroke.
• • Patient position, hyperventilation, hyperosmolar therapy, and rarely, barbiturate coma may be used, as in patients with increased ICP secondary to closed head injury.
  • Recent reports of hemicraniectomy to treat life-threatening ICP have suggested that these patients have shorter ICU stays and a lower mortality rate if surgery is performed before clinical deterioration. One randomized clinical trial did not confirm these benefits.
• Selected patients with either hemorrhagic transformation or intracerebral hemorrhage after thrombolytic therapy may benefit from surgical evacuation of the hematoma.
• If neurosurgical care is not available in house, a transfer policy is encouraged to expedite patient transfer when neurosurgical expertise is needed.

Consultations

Consultations are tailored to individual patient needs.

• In the first hours of acute stroke, an experienced professional sufficiently familiar with stroke or a stroke team should be available within 15 minutes of the patient's arrival in the emergency department.
• Often, physical medicine and rehabilitation (PM&R), occupational therapy, physical therapy, and speech therapy experts are consulted within the first day of hospitalization.
• Consultation of cardiology and vascular surgery or neurosurgery may be warranted based on the results of TTE/TEE, carotid duplex scanning, neuroimaging, and clinical course.
• During hospitalization, additional useful consultations include home health care coordinator, rehabilitation coordinator, social worker, psychiatrist (commonly for depression), and dietitian.

Diet

• Patients with acute stroke are at great risk of aspiration. All patients should remain NPO until a swallowing assessment is performed.
• Because of dysphagia, a temporary feeding tube may be required.
• If the patient remains at a significant aspiration risk for the foreseeable future, a percutaneous endoscopic gastrostomy (PEG) feeding tube may be required.
• A dietitian can help identify a diet that not only addresses the aspiration risk but also ensures adequate caloric intake to help prevent poststroke malnutrition.
• The dietitian also must consider special dietary needs of patients with hypertension, diabetes mellitus, and hyperlipidemia.

Activity

Activity is tailored to the severity of stroke.

• Aspiration precautions, with the head of the bed elevated to 30°, need to be observed.
• Physical therapy will test and suggest level of activity. This should be performed within the first 24 hours of hospitalization.
• Increase activity if tolerated as per the suggestions of the rehabilitation coordinator, with the goal of mobilizing the patient as early as possible. At discharge, encourage patients to increase activity as tolerated.

Medication

While only one drug, t-PA, has demonstrated efficacy and effectiveness in treating AIS and is approved by the US Food and Drug Administration (FDA), other medications are equally important. National consensus panels have included antihypertensives, anticonvulsants, and osmotic agents in their recommendations. Additional agents may be required for comorbid illnesses in many patients with stroke.

Drug Category: Antihypertensives

Optimal blood pressure management in acute stroke remains subject to some debate. Treatment parameters largely depend on whether the patient is a candidate for thrombolytic therapy. While the target blood pressures may differ, the therapeutic agents are largely the same.

Drug Name	Labetalol (Normodyne)
Description	Adrenergic receptor-blocking agent with both nonselective beta-adrenergic and selective alpha1 competitive receptor-blocking actions. Produces dose-related decreases in blood pressure without inducing reflex tachycardia.
Adult Dose	10-20 mg IV over 1-2 min; may repeat or double q10min; total dose not to exceed 150 mg May initiate IV drip at 1-2 mg/min and increase to 2-8 mg/min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bronchial asthma; heart block; cardiac failure; cardiogenic shock; symptomatic bradycardia; hypotension
Interactions	Decreases effect of diuretics and increases toxicity of methotrexate, lithium, and salicylates; may diminish reflex tachycardia resulting from nitroglycerin use without interfering with hypotensive effects; cimetidine may increase blood levels; glutethimide may decrease effects by inducing microsomal enzymes
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in impaired hepatic function; discontinue therapy if signs of liver dysfunction; in elderly patients, response rate may be lower and incidence of toxicity higher

Drug Name	Enalapril (Vasotec)
Description	Angiotensin-converting enzyme (ACE) inhibitor. By inhibiting ACE, decreases circulating angiotensin II levels and suppresses renin-angiotensin-aldosterone system, lowering overall blood pressure.
Adult Dose	0.625-1.25 mg IV; may repeat if inadequate response
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; history of ACE-induced angioedema or idiopathic or hereditary angioedema; acute renal failure; hyperkalemia
Interactions	NSAIDs may reduce hypotensive effects; may increase digoxin, lithium, and allopurinol levels; rifampin decreases levels; probenecid may increase levels; diuretics may increase hypotensive effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment, valvular stenosis, or severe CHF

Drug Name	Nicardipine (Cardene)
Description	A calcium channel blocker, inhibiting calcium ion influx into vascular smooth muscle and myocardium.
Adult Dose	Start 5 mg/h IV, increase by 2.5 mg/h q5-15min to a maximum of 15 mg/h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90>
Interactions	May increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia and a decrease in cardiac output; when administered with beta-blockers, may increase cardiac depression; cimetidine may increase levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in impaired renal or hepatic function; may increase LFTs, and hepatic injury may occur.

Drug Name	Sodium nitroprusside (Nitropress)
Description	Vasodilator that decreases peripheral vascular resistance by direct action of arteriolar smooth muscle. Also decreases venous return through venous dilation.
Adult Dose	0.5 mcg/kg/min IV; slowly titrate within range of 0.5-10 mcg/kg/min; not to exceed 3.5 mg/kg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypertension secondary to arteriovenous shunts or coarctation of aorta
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in increased ICP, hepatic failure, severe renal impairment, and hypothyroidism; in renal or hepatic insufficiency, levels may increase and can cause cyanide toxicity; has ability to lower blood pressure and thus should be used only in those patients with mean arterial pressures >70 mm Hg

Drug Category: Antiplatelet agents

Besides thrombolytics, aspirin is the only other therapeutic agent shown to improve outcome in acute stroke. This class of medications is well known to decrease the risk of stroke recurrence.

Drug Name	Aspirin (Anacin, Bayer Aspirin, Ecotrin, Ascriptin)
Description	Add to treatment if not t-PA candidate. Produces irreversible antiplatelet activity by inhibiting cyclooxygenase, which produces thromboxane A2, a potent platelet activator. Studies have shown that aspirin, started within 48 h of stroke onset and in doses of 50-325 mg/d, reduces risk of early recurrent stroke.
Adult Dose	50-325 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bleeding disorders; liver damage; hypoprothrombinemia; vitamin K deficiency; asthma Because of association with Reye syndrome, do not use in children ( <16 y) with flu Do not administer in first 24 h in patients with stroke who received thrombolytic therapy, though administration of aspirin prior to t-PA is not contraindication
Interactions	Antacids and urinary alkalinizers may decrease effects; corticosteroids decrease serum levels; with anticoagulants, additive hypoprothrombinemic effects and increased bleeding time may occur; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, history of blood coagulation defects, or taking anticoagulants

Drug Category: Anticonvulsant agents

While seizures associated with stroke are relatively uncommon, recurrent seizures may be life threatening. Generally, agents used for treating recurrent convulsive seizures are also used in patients with seizures after stroke. Benzodiazepines, typically diazepam and lorazepam, are the first-line drugs for ongoing seizures.

Drug Name	Diazepam (Valium)
Description	Act on GABA receptor complex in limbic system and thalamus, producing calming effect. Useful in controlling active seizures and should be augmented by longer-acting anticonvulsants, such as phenytoin or phenobarbital.
Adult Dose	5 mg IV q5-10min; total dose not to exceed 20 mg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; acute narrow-angle glaucoma or open-angle glaucoma
Interactions	Phenothiazines, barbiturates, alcohols, and MAOIs increase CNS toxicity; drugs that impair hepatic function, such as cimetidine, may increase risk of sedation
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause significant sedation and obscure neurologic examination findings; caution in impaired hepatic function; caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Drug Name	Lorazepam (Ativan)
Description	Short-acting benzodiazepine with moderately long half-life. Has become drug of choice in many centers for treating active seizures.
Adult Dose	1-4 mg IV over 2-10 min; may repeat q10-15min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; acute narrow-angle glaucoma
Interactions	Alcohol, phenothiazines, barbiturates, and MAOIs increase CNS toxicity; valproate or probenecid may increase serum concentrations
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal, pulmonary, or hepatic impairment, myasthenia gravis, organic brain syndrome, altered mental status, alcohol intoxication, or Parkinson disease

Drug Category: Antipyretic agents

Hyperthermia in acute stroke is potentially harmful and should be treated. Agents with potential bleeding risk should be avoided if possible.

Drug Name	Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)
Description	Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body-heat via vasodilation and sweating.
Adult Dose	325-1000 mg PO/PR q4-6h; not to exceed 4 g/24 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; known G-6-P deficiency; significantly impaired liver function
Interactions	Rifampin can reduce analgesic effects; barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Hepatotoxicity possible in chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; acetaminophen contained in many OTC products and, combined, these products may result in cumulative acetaminophen doses exceeding recommended maximum dose

Drug Category: Fibrinolytic agents

Tissue plasminogen activator is a fibrinolytic protein that is produced normally by the endothelial lining of blood vessels. It is an enzyme (serine protease) that converts plasminogen to plasmin in the presence of fibrin but produces limited conversion of plasminogen in the absence of fibrin. When introduced into the systemic circulation at pharmacologic concentration, it binds to fibrin in the thrombus and converts the entrapped plasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis.

While several new fibrinolytic agents have been introduced for AMI, only alteplase has received FDA approval in treating AIS.

Drug Name	Alteplase (Activase)
Description	Commercially manufactured recombinant DNA fibrinolytic protein approved for treatment of AMI, AIS, and acute massive pulmonary embolism.
Adult Dose	0.9 mg/kg IV; not to exceed 90 mg/dose; infuse over 60 min with 10% of total dose administered as initial IV bolus over 1 min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active internal bleeding; stroke within last 3 mo; recent intracranial or intraspinal surgery or trauma; intracranial hemorrhage on pretreatment evaluation; suspicion of subarachnoid hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm; bleeding diathesis; severe uncontrolled hypertension
Interactions	Drugs that alter platelet function (eg, aspirin, dipyridamole, clopidogrel, abciximab) may increase risk of bleeding prior to, during, or after alteplase therapy Note that criteria for use of IV t-PA preclude use of antiplatelet or antithrombotic agents for 24 h following t-PA infusion
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Noncompressible arterial punctures and internal jugular and subclavian venous punctures must be avoided to minimize bleeding from noncompressible sites; in event of serious bleeding, immediately discontinue alteplase; monitor patients for allergic-type reactions, such as anaphylactoid reaction, laryngeal edema, rash, and urticaria