A 74-year-old woman with a history of atrial fibrillation on warfarin therapy came to the emergency department (ED) 1 hour after the sudden onset of aphasia and right-sided weakness. A non-contrast CT scan of the brain revealed blurring of the left gray-white junction with no hemorrhage, consistent with an acute left middle cerebral artery ischemic stroke. Less than 3 hours had elapsed since the onset of her symptoms, making her a potential candidate for thrombolysis. There were no contraindications to tissue plasminogen activator (tPA) administration at the time, but laboratory results, including a complete blood count (CBC) and coagulation studies, were pending.

In order to expedite treatment (crucial because research finds benefit for thrombolysis in acute stroke only if administered in the first 3 hours; see below), the ED physician wrote an order for an appropriate dose of intravenous (IV) tPA and asked a nurse to obtain the dose from the pharmacy. The nurse returned from the pharmacy and placed the medication at the patient’s bedside. A second ED nurse caring for the patient read the order in the patient’s chart and administered the tPA bolus. Five minutes later, the lab results returned—the INR was elevated at 4.5, an absolute contraindication to thrombolytic therapy.

The patient was transferred to the neurological ICU. She underwent serial CT scanning, which did not show hemorrhagic conversion of her ischemic stroke. She didn’t suffer any other bleeding complications, but she was unable to receive many elements of standard ischemic stroke care, such as permissive hypertension. Eventually, she died of stroke-related complications.

by Susan C. Fagan, PharmD

The use of tPA in acute ischemic stroke patients has been shown to improve the likelihood of an excellent outcome (ie, minimal or no disability) at 90 days by 30%.(1) In clinical practice, the benefits have been shown to be similar, as long as a strict protocol is followed.(2) The therapy is recommended for ischemic stroke patients meeting criteria and presenting early enough to be treated within 3 hours of the onset of symptoms.(3,4) After that narrow window of time, the potential benefits of thrombolysis are thought to be outweighed by the real risk of hemorrhage (up to 15% or more).(5,6) This means that “time is brain” in the management of acute stroke—clinicians have only a short time to assess a patient’s symptoms, confirm that they are due to stroke and that the patient is eligible for thrombolysis, and rule out any condition, such as coagulopathy or preexisting bleeding, that would be a thrombolysis contraindication.

This patient appears to have met criteria for the administration of tPA and might well have benefited from treatment. However, in the rush to administer the tPA in the 3-hour time window, she was given the tPA before her coagulation studies were known. Luckily, she did not suffer any obvious or immediate consequences, but the administration of tPA to a patient whose INR was supratherapeutic (above 3) undoubtedly placed her at increased risk for bleeding complications.

Because weighing the risks and benefits of tPA administration in acute ischemic stroke is complex, institution-specific protocols have been developed, based on the published clinical trial demonstrating efficacy.(1) Unfortunately, protocol deviations occur commonly in the community—in more than 50% of patients treated in some early series.(2,5,6) When examined in a meta-analysis of studies of tPA in routine clinical practice, high rates of protocol deviations were associated with increased in-hospital mortality.(2) The most common protocol deviations were treatment beyond the 3-hour window, use of antithrombotic therapy within 24 hours of tPA administration, and failure to follow blood pressure parameters or monitoring schedule.(5,6) In one study, 10% of the violations involved tPA administered to patients with a “bleeding diathesis,” like the patient in this case.(5)

Thrombolysis in the setting of acute stroke is an urgent, essential, and yet risky intervention for eligible patients. The Institute of Safe Medication Practices (ISMP) considers tPA a “high-alert” medication (7)—one that bears a heightened risk of causing significant patient harm when it is used in error. A recent commentary proposed recommendations to limit errors associated with these medications, focusing on thrombolysis.(8) The principles are listed in the Table.

Is there any way to improve patient safety in the area of acute stroke management? The good news is that instituting a quality improvement effort in acute stroke care, involving education and streamlining processes of care, can drastically reduce protocol violations and improve both the numbers and safety of patients treated.(9) In a recent study, a community-wide quality improvement effort reduced protocol violations from 50% to 19% in a year-long effort.(9) The specific interventions that were effective included improving documentation and communication. Standardized orders and checklists were used (see Figure), with inclusion and exclusion criteria. Most high-volume EDs utilize tPA “kits,” which include order forms, inclusion and exclusion criteria, and the medication. As well, many institutions use a dedicated “stroke team.” Stroke teams consist of nurses practicing in emergency, critical care, and specialized neurological or stroke units; general neurologists; emergency physicians; radiologists; speech-language, physical, and occupational therapists; clinical pharmacists; and nutrition support dietitians. Ongoing, intensive education of providers involved in the care of acute stroke patients is essential.

Unfortunately, the incidence of medication errors in EDs has been estimated to be 12.6% of elderly patients (10) and up to 17% of pediatric emergency patients.(11) Although involvement of a clinical pharmacist in a multidisciplinary team has been shown to reduce adverse events and reduce mortality (12), this tactic is not practical in all ED settings. Diligent attention to the systems of care for administration of a risky, but highly beneficial, medication in a narrow population, such as tPA for stroke, can maximize the benefit to patients.

Take-Home Points

• Thrombolysis for acute stroke can be an effective and safe treatment if strict medication protocols are followed.
• The safe administration of tPA to patients with acute ischemic stroke depends on a well-functioning team that has the necessary tools and has practiced and perfected their roles, both individually and collectively.
• Institutions should utilize standardized orders and checklists with inclusion and exclusion criteria in the care of acute stroke patients.

Susan C. Fagan, PharmD
Professor of Pharmacy
University of Georgia

1. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-7.
[ go to pubmed ]

2. Graham GD. Tissue plasminogen activator for acute ischemic stroke in clinical practice: a meta-analysis of safety data. Stroke. 2003;34:2847-50.
[ go to pubmed ]

3. Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:483S-512S.
[ go to pubmed ]

4. Adams HP Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003;34:1056-83.
[ go to pubmed ]

5. Bravata DM, Kim N, Concato J, Krumholz HM, Brass LM. Thrombolysis for acute stroke in routine clinical practice. Arch Intern Med. 2002;162:1994-2001.
[ go to pubmed ]

6. Katzan IL, Furlan AJ, Lloyd LE, et al. Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA. 2000;283:1151-8.
[ go to pubmed ]

7. ISMP’s list of high-alert medications. ISMP Web site. December 2003. Available at: [ go to related site ]. Accessed February 10, 2005.

8. Paparella S. Thrombolytic therapy: no room for error. J Emerg Nurs. 2004;30:348-50.
[ go to pubmed ]

9. Katzan IL, Hammer MD, Furlan AJ, et al. Quality improvement and tissue-type plasminogen activator for acute ischemic stroke: a Cleveland update. Stroke. 2003;34:799-800.
[ go to pubmed ]

10. Caterino JM, Emond JA, Camargo CA Jr. Inappropriate medication administration to the acutely ill elderly: a nationwide emergency department study, 1992-2000. J Am Geriatr Soc. 2004;52:1847-55.
[ go to pubmed ]

11. Kozer E, Seto W, Verjee Z, et al. Prospective observational study on the incidence of medication errors during simulated resuscitation in a paediatric emergency department. BMJ. 2004;329:1321.
[ go to pubmed ]

12. Position paper on critical care pharmacy services. Society of Critical Care Medicine and American College of Clinical Pharmacy. Pharmacotherapy. 2000;20:1400-6.
[ go to pubmed ]

Table. Recommendations to limit errors associated with thrombolysis.

Figure. Sample stroke history and checklist. Available at http://www.stroke-site.org/pathways/stroke_neuro_history.pdf

Click on the thumbnail for a full view of the figure.