ABSTRACT & COMMENTARY
Tissue Plasminogen Activator and Acute Ischemic Stroke Reviewed
By Eric C. Walter, MD, MSc
Pulmonary and Critical Care Medicine, Northwest Permanente and Kaiser Sunnyside Medical Center, Portland
Dr. Walter reports no financial relationships relevant to this field of study.
This article originally appeared in the September 2014 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor Emeritus, Pulmonary and Critical Care Medicine, University of Washington, Seattle, and Dr. Thompson is Associate Professor of Medicine, University of Washington, Seattle. Drs. Pierson and Thompson report no financial relationships relevant to this field of study.
SYNOPSIS: The authors present an updated review of the use of tissue plasminogen activator in patients with acute ischemic stroke.
SOURCE: Fugate JE, Rabinstein AA. Update on intravenous recombinant tissue plasminogen activator (TPA) for acute ischemic stroke. Mayo Clin Proc 2014;89:960-972.
The use of tissue plasminogen activator (TPA) in acute ischemic stroke is not new. The landmark randomized, controlled trial establishing the effectiveness of intravenous TPA was published in 1995.1 This well-written review summarizes what we have learned about TPA use in the 2 decades since this publication.
In the original trial, the use of TPA within 3 hours of symptom onset improved the chances of a complete or nearly complete neurologic recovery at 3 months by at least 30% (26% in the placebo group vs. 39% in the TPA group). Numerous subsequent studies have confirmed these results. Studies have also shown that earlier TPA use is associated with improved neurologic outcomes, decreased risk of intracranial hemorrhage (ICH), and lower mortality. For every 15 minutes from symptom onset until TPA administration, the risk of intracranial hemorrhage and mortality increases. Time lost truly is brain lost.
The most devastating complication from TPA is ICH. In the original trial, ICH occurred in 6.4% of patients who received TPA. This equates to about 1 in 15 patients. Subsequent studies have confirmed the low incidence of ICH following TPA with reported rates as low as 1.7% for symptomatic ICH at 24 hours. TPA is more likely to cause severe ICH in patients who are older and/or have severe neurologic deficits or large areas of ischemia at presentation. Since these patients are already at high risk of death or severe disability even without TPA, few patients are ultimately harmed by TPA. Because of this, the number needed to harm is estimated to be 1 in 126. Other risks of TPA include angioedema (1-5%) and other rare life-threatening complications.
The most important part of patient selection is to determine the exact time of symptom onset — defined as the exact time a patient was last at their baseline or symptom free. The ideal window is less than 3 hours from symptom onset, but studies have shown that TPA is still effective when given at up to 4.5 hours in certain populations. Very limited testing is needed prior to administration of TPA. A non-contrast head CT is required to exclude ICH and large established infarction, both of which are contraindications. Blood glucose concentration is required to exclude hypoglycemia as a cause of symptoms. Other laboratory testing, including coagulation testing, is not needed unless patients are taking anticoagulants or have a history of thrombocytopenia, liver disease, or hematologic disorders. In general, TPA should be administered if patients have stroke-like symptoms, even if it is not clear if the symptoms are due to stroke. The risk of symptomatic ICH is extremely low if a patient’s symptoms are due to seizures, migraines, or functional disorders.
POST ADMINISTRATION CARE
All patients should be admitted to a specialized stroke unit or ICU after receiving TPA. Neurologic exams should be done every 15 minutes for the first 2 hours, then every 30 minutes for the next 6 hours, and then hourly until 24 hours post administration. Blood pressure should be maintained < 180/105 mmHg. Invasive procedures should be avoided, or at least delayed for several hours, to reduce the risk of bleeding. Antiplatelet agents may be started 24 hours after TPA to help prevent recurrent stroke.
If a patient has a decline in neurologic status, TPA administration should be stopped and repeat head CT obtained immediately to exclude ICH. Systolic blood pressure goal should be lowered to < 160 mmHg, and complete blood count, coagulation labs, and a type and screen drawn. Treatment for ICH depends on the extent of bleeding. Small petechial hemorrhages, especially if found incidentally, should be monitored but generally do not require treatment. Larger parenchymal hemorrhages may require reversal of TPA. While admitting there are no universally accepted guidelines for TPA reversal, the authors suggest that cryoprecipitate be given for fibrinogen levels < 150 mg/dL, platelets should be transfused for platelet counts < 100 × 109/L, and anti-fibrinolytics such as tranexaminic acid should be considered. Neurosurgical intervention may be required depending on the site and size of bleeding.
The authors of this review are clearly advocating for increased use of TPA, noting that only about 3-5% of patients with acute ischemic stroke receive TPA. They support this point of view with well-referenced data. However, it is important to consider that reviews such as this are always influenced by the biases and preferences of the authors.
The intensivist’s involvement in TPA cases is often limited either to the mundane 24 hours of ICU observation or to the nerve-wracking response to devastating complications. This review is helpful for both scenarios. The discussions of fibrinolytic reversal and of treatment of ICH will be of particular interest to intensivists. It would have been nice to have some discussion related to the risks and treatment of non-intracranial hemorrhage and to have more discussion related to the use of specialized stroke units for observation of post-TPA patients rather than in the ICU. Nevertheless, this was a well written, easy-to-read review on an important topic in critical care.
1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587.