Abstract:  Thrombolytic therapy in the treatment of acute ischemic stroke has been associated with a high incidence of intracranial hemorrhage for many years.  New studies show that certain types of thrombolytic drugs used at the right time in the right amounts can prevent brain cell death and increase favorable outcomes at three months.

Introduction
 

    The use of intravenous thrombolytic therapy to treat cerebral vascular accidents caused by embolism is controversial.  Many practitioners believe the number of good outcomes outweigh the risk of intracranial hemorrhage.  Others feel that sacrificing even a few for the potential benefit of others is wrong.  In this paper, I plan to discuss current treatments for CVA, thrombolytic drugs available, studies done on the use of thrombolytics in CVA, protocols in thrombolytic therapy, and the implications for rehabilitation nursing.

CVA, Treatments, and Outcomes

    Essentially, there are two types of cerebral vascular accidents; hemorrhagic and ischemic.  Hemorrhagic strokes, also known as “red strokes,” are associated with hypertension, and occur when a cerebral blood vessel ruptures (Hansen, 1998).  Hemorrhagic strokes are outnumbered by ischemic strokes by a margin of nearly three-to-one (Heart and Stroke Statistical Update, 1998).  Hemorrhagic strokes can be classified as intracerebral hemorrhage or subarachnoid hemorrhage.  Intracerebral hemorrhage (ICH) results from bleeding into the interstitium of the brain, while subarachnoid hemorrhage results from bleeding into the subarachnoid space (Hansen, 1998).  Both conditions are very serious and usually require surgical intervention.  Once the client is stable, treatment of hemorrhagic stroke includes clipping of the ruptured vessel and evacuation of the blood in the cavity created (Hansen, 1998).  Or, if the hemorrhage is small enough, and the body can halt the blood loss, the CVA may be allowed to resolve itself.
    Ischemic strokes, also known as “white strokes,” are associated with atherosclerosis and are a result of some type of blockage in a cerebral artery.  Types of ischemic stroke include embolic and transient ischemic attacks (TIAs).  Embolic strokes can result from a blood clot formed elsewhere in the body (besides the brain) which travels to a cerebral artery (usually the middle cerebral artery) and occludes the vessel causing hypoxia of the area for which the vessel perfuses (Hansen, 1998).  Some collateral circulation is possible, but cell death is ultimately the consequence of an embolic stroke.
Transient ischemic attacks (TIAs) are “ministrokes” that can precede a full-blown stroke.  Severe occlusion (greater than 75%) of one or both of the carotid arteries can cause TIAs.  TIAs also “may result from spasm at sites of plaque or from miniemboli composed of plaque fragments or blood clots” (Hansen, 1998).  The difference between TIAs and embolic occlusive (full-blown) strokes is that the symptoms of TIAs last less than 24 hours, whereas embolic symptoms persist longer. Until recently, treatment of ischemic stroke was limited to prevention of further strokes by use of anti-coagulant drugs.  In a study by Richard Kay and his colleagues, low-molecular-weight heparin was effective in improving outcomes of stroke victims if given within 48 hours of the onset of symptoms (Kay et al, 1995).  Following the diagnosis of an ischemic stroke, the area of the brain affected would die secondary to hypoxia, and reperfusion was thought to be impossible.
    Almost a third of stroke victims die during the first three weeks after the stroke (Goldstien, 1994).  Hemorrhagic strokes are associated with a higher incidence of fatality than that of ischemic stroke (AHA, 1998).  Of those who survive, only 12.6% will have minimal or no disability at three months.  “Minimal or no disability at 3 months was defined [in the study] as 95 or 100 on the Barthel Index, <1 on the NIHSS and Modified Rankin Scale, and 1 on the Glasgow Outcome Scale” (NINDS, 1998).  Annually, stroke costs the US nearly $40.9 billion.  More than half of this $40.9 billion was made up of direct health care expenses including hospital stays, long-term care, physician/other professionals, drugs, and home health/other medical durables.  The remainder was made up of lost productivity/morbidity and lost productivity/morality (Heart and Stroke Statistical Update, 1998).
    Thrombolysis of ischemic stroke was largely abandoned in the 1960s due to the high incidence of death by cerebral hemorrhage (Caplan et al, 1997).  The last trial of thrombolytic drugs (other than t-PA) was MAST-I, performed in Australia.  “Only 622 patients of the estimated 1,500 needed for completion were enrolled when the trial was discontinued upon the recommendation of the Data Monitoring Committee.”  The study’s preliminary results showed that patients treated with streptokinase and ASA had a significantly greater chance of death than patients that were not given streptokinase nor ASA did (NINDS, 1995).
 

Thrombolytic Drugs

    Thrombolytics are available in four major types: streptokinase, urokinase, anistreplase, and activase® (t-PA).  The first of these, streptokinase is derived from filtered enzymes of beta-hemolytic streptococci.  Streptokinase works by combining with plasminogen and converting it to plasmin, which lyses fibrin clots, fibrinogen, and other plasma proteins.  This action is fast, and may last up to 12 to 24 hours.  Streptokinase is used in lysis of coronary artery thrombi, acute massive pulmonary emboli, deep vein thrombi, and clearing of occluded arteriovenous cannulae as an alternative to surgical revision (Gahart & Nazareno, 1998).  Streptokinase is contraindicated in acute ischemic stroke because of its systemic effects, which include decreased blood viscosity, altered platelet function, and anticoagulant action long after the drug itself has been degraded into its constituent parts.  Spontaneous hemorrhage may occur, and bleeding following streptokinase therapy is very difficult to control (Spencer et al, 1993).  A low-grade fever is common with streptokinase, as it almost always initiates an allergic reaction.  In fact, Benadryl 50 mg IV is recommended for prophylactic treatment of the immune response (Gahart & Nazareno, 1998).
     “Urokinase is a trypsinlike serine protease extracted from human urine”.  Similar in action to streptokinase, urokinase causes an increase in plasmin levels throughout the body.  However, urokinase does not affect platelet function.  Like streptokinase, urokinase is used in treatment of AMI, PE, and DVT.  But urokinase is especially useful in patients who have previously received streptokinase, as streptokinase would be less effective in a person who has developed antibodies against it.  Again, urokinase can cause systemic anticoagulation for 12-24 hours and is contraindicated for use in acute ischemic stroke.  One benefit of urokinase is that it does not seem to have the allergic properties that streptokinase does (Spencer et al, 1993).
 “Anistreplase (Eminase) is a complex derived from lysplasminogen and streptokinase” (Spencer et al, 1993).  Anistreplase acts similar to streptokinase, but has much less systemic effects.  One study, (Altman, 1991) has shown that the three drugs---streptokinase, t-PA, and eminase---have equal effectiveness in the treatment of people who have already had one MI.
     Tissue plasminogen activator (t-PA) is “a purified glycoprotein of 527 amino acids, synthesized using complementary DNA for human tissue-type plasminogen activator obtained from a human melanoma cell line” (Kongable, 1997).  This drug acts in the presence of thrombin in formed clots.  T-PA increases plasmin at the clot site, and therefore does not produce systemic anticoagulation or fibrinolysis (Clark, Queener, & Karb, 1997).  As stated by Kongable, one reason t-PA causes less cerebral hemorrhage than other thrombolytic drugs is that its half-life is less than five minutes, and t-PA has a duration of action of only 25-50 minutes.  Additionally, excessive t-PA in the blood is inactivated by alpha2-antiplasmin (Hansen, 1998).  T-PA is the only drug approved by the FDA for use in lysis of acute ischemic stroke (Gahart & Nazareno, 1998).  Solely Genentech produces T-PA, whose tradename is Activase®, a company that has been doing recombinant DNA research since 1987.
 

Studies on Thrombolytics in CVA

     Various studies on thrombolytic therapy have been conducted, with a wide variance of results.  Five studies which were recently done include the Multicentre Acute Stroke Trial—Europe (MAST-E), Multicentre Acute Stroke Trial—Italy (MAST-I), Australian Streptokinase (ASK) Trial, European Cooperative Acute Stroke Study (ECASS), and National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study. Three of these studies, MAST-E, MAST-I, and ASK used intravenous streptokinase therapy within 4-6 hours after stroke.  These three trials were stopped early because the incidences of death and/or ICH were shown to be greater than with placebo.  Based on this finding, intravenous streptokinase is not recommended for treatment of acute ischemic stroke (Koller, 1998).
     The two remaining studies, ECASS and NINDS tested the effectiveness of t-PA therapy.  The findings in these two studies offer conflicting data.  It must be noted however, that these two studies used very different criteria.  In ECASS, victims of stroke were given 1.1 mg/kg intravenous t-PA or placebo within six hours of symptom onset.  In the NINDS trial, stroke patients were randomly assigned to receive 0.9 mg/kg of intravenous t-PA or placebo within three hours of symptom onset.  Also, the NINDS trial allowed for a maximum of 90 mg.
     These two studies were measured using four different assessment tools: the Barthel index, modified Rankin scale, Glasgow outcome scale, and the national institutes of health stroke scale (NIHSS).  The modified Rankin scale and the Glasgow outcome scale use similar rating systems, while the Barthel index measures activity of daily living, and the NIHSS converts neurologic examination results into a numeric scale.  A score of zero in any given area represents normal function in that area.
     The results of these two studies are strikingly different.  In the NINDS trial, an extra 11-13% of stroke patients had no disability after three months.  A major complication of any thrombolytic therapy is hemorrhage.  In the NINDS trial, symptomatic hemorrhage occurred in 6.4% of t-PA treated patients compared with 20% in the ECASS trial.  Overall, there was no overall increase in mortality compared with placebo in the NINDS trial (Grotta, 1997).
     The wide disparity between these two studies can be explained by examining their methodology for administration and criteria for selecting patients.  The ECASS study’s patients received t-PA within six hours of symptom onset (median 4.4 hours), while in the NINDS study; t-PA was not given beyond three hours.  The NIH guidelines recently recommended a “door-to-needle” time of 60 minutes or less for acute stroke patients (Chiu et al, 1998).  Additionally, a larger dose (1.1 mg/kg) was given to patients in the ECASS study, without a maximum dose.  While in the NINDS trial, 0.9 mg/kg was used with a maximum dose of 90 mg (Grotta, 1997).  These studies have shown that larger doses of t-PA can lead to increased risk of hemorrhage.  The results of these two studies have led to strict screening and protocols being used.

Protocols for Using Thrombolytics in CVA

     T-PA has been used in acute myocardial infarction since 1983 (Gwynn, 1993).  Therefore, much of what makes up t-PA protocols in acute ischemic stroke comes from what has been learned from its use in AMI.
     For obvious reasons, t-PA is contraindicated for use in intracranial hemorrhage.  Other contraindications include rapidly improving or minor symptoms (e.g. TIA), and symptoms that mimic stroke such as hypoglycemia (NINDS, 1995).  Few patients meet the strict guidelines set forth by the FDA to receive t-PA for acute ischemic stroke.  The largest exclusion criterion is the three-hour rule.  Patients must be treated within three hours of onset of symptoms in order to reduce the risk of intracranial hemorrhage.  Many stroke victims wake up experiencing symptoms and therefore cannot tell when their symptoms began.  Other patients experiencing symptoms of stroke do not rush to medical treatment because they are not aware that stroke is a treatable condition (Gwynn, 1993).
     To be eligible for t-PA treatment, a CT scan must rule out intracranial hemorrhage.  Also, patients who have had another stroke or head trauma within the last three months cannot receive the drug.  Patients who have undergone major surgery in the last 14 days; have a history of ICH; have a systolic blood pressure above 185 mm Hg or diastolic blood pressure above 110 mg Hg; have had gastrointestinal hemorrhage or urinary tract hemorrhage within the previous 21 days; have had arterial puncture at a noncompressible site within the previous seven days; or have had a seizure at the onset of the stroke can not receive t-PA therapy (NINDS, 1995).
    T-PA is given by intravenous route after reconstitution with non-bacteriostatic sterile water for injection (Gahart & Nazareno, 1998).  The patient receives 0.9 mg/kg with a maximum dose of 90 mg.  10% of the total dose is given over one minute and the remainder is given over 60 minutes.  T-PA for acute ischemic stroke is given only once, unlike t-PA treatment for patients with acute myocardial infarction which may continue for several hours after the first dose (Gwynn, 1993).

Implications for Rehabilitation Nurses

     Many organizations have supported the use of t-PA in treatment of ischemic stroke.  These organizations include the American Heart Association, the American Academy of Neurology, and the National Stroke Association, but they also emphasize that t-PA carries risks of hemorrhage (Koller, 1998).
Patients who have suffered a stroke are often admitted to rehabilitation centers, either on an inpatient or outpatient basis.  Whether or not a patient received t-PA therapy, rehabilitation for a patient exhibiting deficits is indicated.  Given that there is no significant difference between patients given t-PA and those given placebo at 24 hours (NINDS, 1995), patients need to be offered emotional support during this time of crisis.  At three months, if the area of the brain affected by the stroke was re-perfused in time, patients may recover with little or no deficits (NINDS, 1995).
     The most important implication for nurses and other health care professionals is education.  The public needs to change its perception of stroke as a non-treatable disorder.  Being able to recognize the early symptoms of stroke and seeking medical treatment may mean the difference between disability and no disability.  Other health care professionals such as doctors, paramedics, and therapists should be made aware of this new treatment for stroke so that policies and procedures may include a more aggressive treatment plan for stroke victims.  Current patients can also benefit from education about how to recognize symptoms of stroke.
     In conclusion, tissue plasminogen activator, if given within three hours of onset of symptoms, can increase favorable outcomes of acute ischemic stroke by as much as 30%. For many, the benefits of thrombolysis of embolism and re-perfusion of brain tissue outweigh the risks of intracranial hemorrhage, but each individual should be assessed on a case-by-case basis.  With peer and public education about current thrombolytic treatments, acute ischemic stroke may one day fall below the number one cause of adult disability.

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