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Overview: hyperacute rt-PA stroke treatment.


Stroke is the third leading cause of death in the United States, being responsible for 150,000 mortalities annually. Approximately 550,000 new strokes occur every year, and there are an estimated 3,000,000 stroke survivors. Stroke is both the leading cause of adult disability and the leading diagnosis for long-term care. Approximately $30 billion is spent annually for stroke survivors with varying degrees of neurological and functional disabilities. Sixteen percent of stroke survivors are institutionalized, while 71% remain vocationally impaired after 7 years; 34% under age 65 years are unemployed.[11] Ischemic stroke, which is caused by thrombotic or embolic blockage of blood flow to the brain accounts for approximately 83% (400,000) of all strokes. The remaining 17% of strokes are hemorrhagic, caused by bleeding into the subarachnoid space or the intracerebral areas of the brain.[16]

Animal models of cerebral ischemia have provided most of the current understanding of brain infarction.[6,13] When ischemic stroke occurs, a complex series of cellular metabolic events immediately arise (Fig 1). The duration, severity and location of focal cerebral ischemia determine the extent of brain infarction and thus, the severity of the stroke.[3] The immediate effect of cerebral ischemia is insufficient oxygen to meet the energy requirements of brain cell metabolism.[8] Neuronal activity ceases with prolonged hypoxia. This ischemic cascade continues as pronounced cellular and neurological dysfunction ensue and excitatory neurotransmitters, such as glutamate and aspartate are released into the extracellular space. The neurotransmitters are free to bind to cell membrane receptors, particularly the N-methyl D-aspartate (NMDA) receptor. Transmembrane channels remain open, allowing an influx of water, sodium and calcium ions. These final events result in cell edema and death.[14]


Stroke Therapy

A search for therapy for ischemic stroke has been ongoing. Thrombolysis in particular has been studied as a potential method of reperfusion. It was thought that thrombolytics given early enough would dissolve the clot and potentially lessen the disabling effects of stroke.[9,16] Recombinant tissue plasminogen activator (rt-PA) is one such thrombolytic agent.

Streptokinase and urokinase were the first two thrombolytic agents approved for clinical use in adults. Urokinase is an enzyme produced-by the kidney and found in urine. It is a potent activator of the fibrinolytic system. Streptokinase is a bacterial enzyme synthesized by group C-beta hemolytic streptococci, but is commonly associated with minor allergic reactions.[4] These agents proved effective in treating massive pulmonary emboli and deep venous thrombosis without excessive complications of systemic hemorrhage. Intracranial hemorrhage was of critical concern in all studies utilizing thrombolytics, and was a key factor in the safety analysis of all clinical indications.[15]

Pro-urokinase, recombinant tissue plasminogen activator (rt-PA), and acylated plasminogen streptokinase complex (APSAC) are thrombolytic agents which were developed by genetic recombination techniques. Through altering selected biochemical properties of the original agent, it was hoped streptokinase and urokinase might be more fibrin-specific and less attracted to fibrinogen. This effect would decrease systemic fibrinolytic activity and lead to fewer hemorrhagic complications.[15]

Pro-urokinase is a pro-enzyme derived from urine using recombinant technology. It is only activated when introduced into the blood stream. APSAC is prepared from pasteurized human plasminogen and streptokinase. The active site of plasminogen has been acylated to render it inert to activation or inhibition by other plasma proteins.[15] These two agents are not proven to be fibrin-specific and have been associated with systemic proteolysis. The mechanism of action of thrombolytic agents is shown in Figure 2.


rt-PA is a new-generation thrombolytic agent, initially tested and approved for use with coronary artery thrombolysis and pulmonary embolism. rt-PA is obtained from melanoma cell cultures or recombinant techniques. It has a half-life of approximately 5 minutes and acts locally on fibrin to convert the entrapped plasminogen to plasmin.[18] rt-PA's ability to reduce infarct size in acute myocardial infarction (AMI) is similarly useful in the treatment of acute ischemic stroke (Table 1). in this instance, lysis of the thrombus in the affected blood vessel enhances reperfusion to the affected brain-tissue, thus improving the patient's neurological condition to normal or near-normal.[1] It is now recognized that the clinical application of rt-PA treatment for acute ischemic stroke is different from that applied to AMI.

Table 1. AIS vs AMI Thrombolytic Therapy
Acute Ischemic Stroke (AIS)

1. Dose:
 Weight based 0.9 mg/kg
 90 mg max

2. Time Window:
 Within 3 hours
 CT scan of the head to eliminate
 intracranial hemorrhage

3. Concurrent Therapies:
 No aspirin, warfarin, heparin for
 24 hours post treatment

4. Medical History Contraindications
 No AMI's pericarditis
 Previous strokes > 3 months

Acute Myocardial Infarction (AMI)

1. Dose:
 Weight based < 67 kg
 100 mg max

2. Time Window:
 0-12 hours
 CT scan not required

3. Concurrent Therapies:
 Aspirin, warfarin, heparin

4. Medical History
 No prior history of stroke
 Prior MI's treatable

Clinical Trials

The potential for thrombolysis in acute cerebrovascular occlusion gave rise to many clinical trials. Mast-E, the Multicentre Acute Stroke Trial-Europe, treated stroke victims with 1.5 million units of streptokinase or placebo over one hour. The trial was stopped due to the high rate of symptomatic hemorrhage and death. Any benefit from treatment was marginal.[19] The Australian Streptokinase Trial (ASK) was a double-blind placebo-controlled trial in which the drug was given within 4 hours of stroke onset. This trial was terminated due to an increase in adverse experiences (severe disability or death) in the streptokinase group.[4] Mast-I, the Multicenter Acute Stroke Trial - Italy, was a controlled, randomized, unblinded trial that compared outcomes among persons enrolled in one of 4 treatment groups. The safety committee stopped the trial after enrolling 622 persons. Mortality at 10 days and symptomatic intracranial hemorrhage were significantly higher among persons treated with streptokinase. The risk of early death or bleeding was particularly high when streptokinase was combined with aspirin.[10]

The European Cooperative Acute Stroke Study (ECASS), was a double-blind placebo-controlled trial with rt-PA. Patients were enrolled within 6 hours from stroke onset, and most were treated more than 3 hours after onset. The dosage administered was 1.1 mg/kg with a maximum dosage of 100 mg. A bolus of 10% of the total dose was given over 1 minute and the remainder over an hour. The study randomized 620 patients between the rt-PA and placebo group. There were no significant differences in the Barthel Index scores between the two treatment groups, however, other predefined endpoints including neurological outcome, speed of recovery and duration of in-hospital stay favored patients treated with rt-PA. Parenchymal hemorrhage, however, was significant among the rt-PA treated patients.[7]

Increasing experience with ultra-early stroke treatment demonstrated that the physiological and metabolic changes that occur between 1-3 hours after cerebral blood flow occlusion cause mild to moderate neuronal dysfunction, some of which could be reversible. Six hours after occlusion, cell damage is more permanent and by 24 hours, cell necrosis begins and continues until pan-necrosis is evident by 48 hours.[5,13] with this in mind, a treatment window of 3 hours from stroke onset was deemed critical.[8]

Thrombolysis with rt-PA seemed the most promising and safest of all the thrombolytics. The NINDS rt-PA Stroke Trial selected rt-PA for use in treatment of ischemic stroke within 3 hours of onset of symptoms. In the dosage escalation phase of the study, 0.9 mg/kg was selected as most safe, with an acceptable risk of hemorrhage; results suggested rt-PA was effective when given within the 3 hour time window.[2] The NINDS study had two parts. In part 1, 291 patients were enrolled in 8 centers in the United States. This double-blind trial compared the performance of rt-PA versus placebo, to be measured by an improvement of 4 points over baseline values in the score of the NIH stroke scale. Part I results did not demonstrate a difference in neurologic amelioration between rt-PA and the placebo at 24 hours from onset of stroke based on the rigid improvement criteria (Table 2). However, there was a significant difference, favorable to rt-PA, after 3 months.[12]

Table 2. NINDS Trial Part 1 24 Hour Improvement in Neurological Deficit
Percentage of patients with
24 hour improvement on 0-90 Min 91-180 Min 0-180 Min
 Activase (n=144) 51% 43% 47%
 Placebo (n=147) 46% 33% 39%
 p Value 0.55 0.20 0.18

Median NIHSS Score at 24 hours 0.90 Min 91-180 Min 0-180 Min
 Activase (n=144) 9 8 8
 Placebo (n=147) 11 12 12
 p Value 0.34 < 0.01 < 0.01

(*) 4 or more point improvement from baseline score or complete resolution of neurological deficit (NIHSS score of 0)

In part 2, 333 patients were enrolled at the same 8 centers. The trial confirmed the findings of Part 1. A global assessment based on a number of outcome scales, including the NIH stroke scale, showed that those patients given rt-PA were at least 30% more likely to have minimal or no disability at 3 months compared with those who received the placebo (Fig 3). rt-PA was approved by the US Food and Drug Administration (FDA) for treatment of ischemic stroke within 3 hours of symptom onset in June 1996.[12]


Clinical Impact

As a consequence of the successful trial and FDA approval, the traditional laissez-faire approach to stroke must be replaced by the emerging view of "Brain Attack" in which time is of the essence. This supplement conveys the message, "Time is Brain," and provides a catalyst for change among health professionals and the general public. The whole community must be educated to consider stroke a "Brain. Attack" and call 911 immediately. The emergency medical services must recategorize stroke patients as high priority, and emergency department (ED) staff must establish a triage for "Code Stroke." Clinical pathways minimize delays to treatment and provide direction for a team approach to care.

The collective experience gained in the NINDS rt-PA Stroke Study is presented in the following articles. The information provided herein is applicable to all acute care hospitals. The essential components include a stroke team, code stroke procedures and health care professionals dedicated to improving understanding of stroke in the community and providing effective treatment with minimum delay. Members of the trial centers truly form a multidisciplinary team. While the essential nature of each contributing center in the study varied, common themes and processes emerged. Some centers had a single treatment location, while others were comprised of multiple enrolling satellites. At one center, the Chairman of Emergency Medicine was the principal investigator, while the majority of center investigators were neurologists. Paradoxically, these differences serve to underscore the similarities at all centers whereby highly developed communication lines and cooperation between neurology and emergency medicine (EM) is a preferred organizational solution for the successful treatment of the stroke patient. As a consequence, the processes employed are generalizable and adaptable to most treatment settings. Some facilities may designate EM physicians with specialist training to supervise the Code Stroke, while at other centers, neurologists working with personnel from EM may hold the primary responsibility.

With the advent of rt-PA treatment of ischemic stroke, nursing care of stroke patients must change. Stroke triage in the ED should be high priority. Triage nurses should notify ED staff physicians immediately, establish intravenous access, draw STAT laboratory studies and transport the patient to an emergency computed tomography (CT) scan to distinguish between ischemic and hemorrhage stroke. This determines the treatment pathway for each stroke type, and dictates proper blood pressure management, frequency of neurological evaluation and cardiac assessment. Patients may be evaluated and treated by nurses in the ED, the critical care setting, neurological acute care or the medical/surgical unit. Those patients treated with thrombolysis require competent nursing care in all clinical settings. A good understanding of the pathophysiology of cerebral ischemia and infarction, the mechanism of thrombolysis and clinical skill in neurological assessment are essential to effective nursing intervention in acute stroke.

The NINDS rt-PA Stroke Trial clinical coordinators have prepared this supplement to promote effective acute stroke intervention. These articles provide important details in the design of acute stroke intervention procedures and the clinical management of patients who receive rt-PA in the early hours after stroke:

* Pathophysiology and Mechanisms of Acute Ischemic Stroke

* Code Stroke: Rapid Transport, Triage and Treatment Using rt-PA Therapy

* Nursing Management of Bleeding Complications Following Thrombolytic Therapy in Acute Ischemic Stroke Nursing Care of Acute Stroke Patients After Receiving rt-PA Therapy

* Using the NIH Stroke Scale to Assess Stroke Patients

* Education to Improve Stroke Awareness and Emergent Response


[1.] Adams HP, Brott TG, Furlan AJ et al: Guidelines for Thrombolytic Therapy for Acute Stroke: A Supplement to the Guidelines for the Management of Patients with Acute Ischemic Stroke. AHA Stroke Council, 1996.

[2.] Brott TG, Haley EC Jr, Levy DE et al: Urgent therapy for stroke. I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992; 23:632-640.

[3.] Caplan LR: Basic pathology, anatomy and pathophysiology of stroke. Pages 23-53 in: Stroke, A Clinical Approach. Butterworth-Heinemann, 1993.

[4.] Donnan GA, Davis SM, Brien RC et al (per pro Australian Streptokinase (ASK) Trial Study Group): Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996; 276(12):961-966.

[5.] Fisher M: The pathophysiology of ischemic stroke. Pages 313-323 in: Clinical Atlas of Cerebrovascular Disorders, Fisher M (editor). Mosby-Year Book Europe, 1995.

[6.] Garcia JH, Yoshida Y, Chen H et al: Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Amer J Pathol 1993; 142:623-635.

[7.] Hacke W, Kaste M, Fieschi C et al (per pro the ECASS Study Group): Intravenous thrombolysis with rt-PA for acute hemispheric stroke. JAMA 1996; 274(13):1017-1059.

[8.] Heiss WD, Rosner G: Functional recovery of critical neurons as related to degree and duration of ischemia. Ann Neurol 1983; 12:294-301.

[9.] Horowitz SH, Zito JL, Donnarumma R, Patel M, Alvin J: Computed tomographic-angiographic findings within the first five hours of cerebral infarction. Stroke 1991; 22(10):1245-1253.

[10.] The Multicenter Acute Stroke Trial-Italy (MAST-I) Group: Randomized controlled trial of streptokinase, aspirin & combination of both in treatment of acute ischemic stroke. Lancet 1995; 346:1509-1514.

[11.] National Stroke Association, 1994.

[12.] NINDS rt-PA Stroke Study Group: rt-PA for acute ischemic stroke. New Engl J Med 1995; 333(24):1581-1587.

[13.] Pulsinelli W: Pathophysiology of acute ischemic stroke. Lancet 1992;339:533-536.

[14.] Raichle ME: The pathophysiology of brain ischemia. Ann Neurol 1983; 13:2-10.

[15.] Ratnoff O, Forbes C: Disorder of hemostasis. Pages 313-329 in: Thrombolytic Therapy, 2nd ed, Bennett B, Gatond O (editors). WB Saunders Co, 1991.

[16.] Rogers SJ, Sherman DG: Pathophysiology and treatment of acute ischemic stroke. Clin Pharmacol 1993; 12:359-376.

[17.] Stroke/Brain Attack Reporter's Handbook. National Stroke Association, 1995.

[18.] Summary of Clinical Data and Product Information for the Management of Acute Ischemic Stroke. Genentech Inc., 1996.

[19.] The Multicenter Acute Stroke Trial-Europe Study Group: Thrombolytic therapy with streptokinase in acute ischemic stroke. New Engl J Med 1996; 335(3):145-150.

Rosario Donnarumman, Gail Kongable, Carol Barch, Janet Braimah, Patti Bratina, Sheila Daley, Karen Rapp, Sharion Sailor, Judith Spilker and the NINDS rt-PA Stroke Study Group

Questions or comments about this article may be directed to: Rosario Donnarumma, RN, MA, Long Island Jewish Medical Center, Department of Neurology, 270-05 76th Avenue, New Hyde Park, New York, New York 11040.
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Title Annotation:Special Issue on rt-PA Stroke Treatment; recombinant tissue plasminogen activator
Author:Donnarumma, Rosario; Kongable, Gail; Barch, Carol; Braimah, Janet; Bratina, Patti; Daley, Sheila; Ra
Publication:Journal of Neuroscience Nursing
Date:Dec 1, 1997
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Next Article:Pathophysiology and mechanisms of acute ischemic stroke.

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