Focus On: Acute Ischemic Stroke

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September 2009

By Amer Aldeen, M.D., and Matthew Pirotte, M.D.  

Learning Objectives

After reading this article, the physician should be able to:

  • Identify the management steps in treating patients suspected of having AIS.
  • Understand the complex issues that determine appropriate candidates to receive thrombolysis.
  • Understand the risks of using rTPA

Acute ischemic stroke (AIS) is defined as permanent brain injury secondary to disruption of blood flow. The incidence of AIS is approximately 700,000 per year, with about 61,000 deaths.1 Although care of the patient with AIS begins with the public (recognition) and EMS (expeditious transport), the formal evaluation and treatment of AIS occur in the emergency department.2 The only approved acute pharmacologic intervention for AIS, intravenous alteplase (rTPA), is unique in the emergency department because of its extremely narrow temporal window and strict contraindications.3 It has been estimated that just 3%-8% of eligible patients with AIS receive rTPA.4 Because of the potential for benefit from this therapy for AIS, the emergency physician must be competent in clinical recognition, rapid initial management, and specialist consultation early in the diagnostic and treatment process.

Pathogenesis and Etiology 

Anything that disrupts the flow of blood to the brain may cause a stroke. Common causes include large vessel atherosclerosis, small vessel disease, and cardioembolic events. More rare causes of stroke include arterial dissection, vasculopathies, hypercoagulable states, hematologic conditions that increase blood viscosity, and septic emboli. Up to 40% of all strokes are cryptogenic.5 

When blood flow to areas of the brain is reduced, neurons begin to die via direct starvation from lack of glucose, failure of ATP production, membrane depolarization, rises in intracellular calcium, and free radical production. Rising synaptic glutamate concentrations also promote elevations in intracellular calcium levels. Membranes degrade, mitochondria break down, and the cellular cytoskeleton fails.6 

As with other emergency diagnoses that focus on arterial obstruction, such as acute myocardial infarction and gonadal torsion, "time is tissue."7 Saver quantified this concept with respect to AIS: Every minute of large-vessel brain ischemia results in the death of 1.9 million neurons and 14 billion synapses. Furthermore, the rate of tissue loss in AIS compared with the normal neuronal decline of aging suggests that brain is "aging" 3 weeks for every minute of ischemia and 3.6 years for every hour.8 


Prompt diagnosis of stroke is essential because of the time-sensitive nature of the only available emergent drug treatment. The National Institute of Neurologic Disorders and Stroke (NINDS) rTPA study group trial showed in 1995 that in a population of 624 patients with AIS, intravenous alteplase administered within 3 hours of the onset of stroke symptoms resulted in better 3-month outcomes than did placebo.7  

Multiple trials have confirmed the NINDS trial findings and established that management of AIS hinges on two basic questions: (1) Is this patient having AIS, and (2) is this patient a candidate to receive intravenous thrombolysis?

Is this patient having AIS? An acute, focal neurologic deficit is the hallmark of stroke. Major strokes involve both motor and sensory components. Symptoms may be sudden and maximal at onset (embolic) or intermittent and stuttering (thrombotic).

Findings in stroke syndromes depend on the territory of brain suffering infarction.

Anterior cerebral artery strokes produce contralateral sensory defects and contralateral weakness most profound in the lower extremities, often with urinary incontinence and dysarthria. Middle cerebral artery strokes produce contralateral sensory loss and weakness and homonymous hemianopsia. Lacunar strokes may produce varied combinations of weakness, sensory deficit, and ataxia.

Vertebrobasilar, or posterior circulation, strokes produce dizziness, vertigo, vomiting, and ataxia, and can cause limb weakness as well. The complaint of isolated dizziness is highly unlikely to be caused by a stroke.9  

The differential diagnosis of AIS includes intracranial hemorrhage (ICH) or mass lesion, migraine, post-ictal paresis (Todd's paralysis), CNS infection, multiple sclerosis, drug intoxication, hypoglycemia, and conversion disorder.10 

Is the patient a candidate for rTPA? Time of onset of the focal neurologic deficit is the most important piece of history. The emergency physician should always attempt to answer the following question: When was the exact onset of stroke symptoms or, if this is unknown, when was the patient last observed to be asymptomatic? If onset of stroke symptoms occurred within 3 hours of evaluation, the goals of immediate management are different from cases that occur outside this window (also see the "Controversies" section below for further clarification).

When patients are seen in the emergency department within 3 hours of stroke symptoms, evaluation should be extremely rapid in a manner similar to trauma resuscitation, focusing on determining candidacy for rTPA. Findings particularly consistent with AIS include speech disturbance, and unilateral weakness, arm drift, and/or lower facial droop.11  

After stroke is suspected based on history and physical examination, prompt imaging of the brain with non-contrast computerized tomography (CT) is indicated. The goal of CT is not necessarily to diagnose AIS, but rather to rule out contraindications to the use of rTPA, such as ICH or mass lesion.12 A more thorough physical examination should never delay performance of the CT, as this may push the patient outside the 3-hour time window where rTPA is considered safe and effective.

The emergency physician should calculate the National Institutes of Health Stroke Scale (NIHSS) score when the history and physical exam strongly suggest AIS and other diagnoses are excluded by CT. The NIHSS will allow the emergency physician both to quantify the stroke in a validated manner and to assist in communication with neurology consultants.13 The NIHSS is available online at

Outside of the 3-hour symptom window, evaluation should be still be emergent, but can follow the standard protocol of focused history and physical exam followed by diagnostic testing and management based on findings.

Further diagnostic testing. See the inset below for a list of suggested ancillary testing in the evaluation of AIS. A chest x-ray is not considered mandatory. One retrospective review of 435 patients with AIS concluded that the admission chest radiograph altered patient management in just 3.8% of cases, and that more than three quarters of these radiographs were technically poor studies.14 

Antihypertensives In AIS 

  • Labetalol: 10-20 mg IV over 1-2 minutes; may repeat x1.
  • Nitropaste: 1-2 inches.
  • Nicardipine infusion: 5 mg/hour, titrate up by 2.5 mg/hour at 5- to 15-minute intervals, maximum dose 15 mg/hour; when desired blood pressure attained, reduce to 3 mg/hour.


Management of the patient with AIS begins in the field. Properly trained EMS providers will recognize the possibility of acute stroke and communicate ahead to the receiving emergency department. Priority actions in the emergency department are listed in the inset below. It is particularly important to rule out hypoglycemia as a cause of a neurological deficit; the blood glucose should be obtained along with the vital signs and corrected as appropriate.

Sequence of Immediate Evaluation in Patients Suspected of AIS  

 (Within 3 hours of symptom onset.) 

  1. Address airway, breathing, circulation, and vital signs.
  2. Obtain IV, draw labs (CBC, chemistry, coagulation profile, cardiac markers, alcohol level) and place on a cardiac monitor.
  3. Check rapid glucose level and give IV glucose as needed.
  4. Confirm the focal neurologic deficit with a brief exam.
  5. Obtain non-contrast CT brain to determine if ICH or mass is present.
  6. Calculate National Institute of Health Stroke Scale (NIHSS) score and consult neurologist.
  7. Other studies may be obtained later (e.g., EKG, urine drug screen).

Once the diagnosis of AIS is confirmed, the emergency physician should make the decision to give rTPA in consultation with neurology specialists (see the "Controversies" section). The specific logistics of rTPA administration are beyond the scope of this article. Instead, the articles will address other management issues related to AIS.

Certain coincident (and modifiable) pathologic perturbations have been associated with worse outcomes in AIS. These include fever, hyperglycemia, and hypertension. The American Heart Association (AHA) has issued Class I recommendations that these conditions be evaluated and treated in the stroke patient.

Fever is defined as a core body temperature greater than 37.5° to 38° C. The AHA recommends that fever in stroke should be treated (though without further specific guidelines). The data to treat fever in AIS are based on observations about the effect of fever on infarct size and worse neurological outcome.15,16,17,18 More formal studies are needed to determine exactly how and when to treat fever in AIS, but it is reasonable to use 1 g of acetaminophen for a temperature greater than 38° C.19 Fever should also prompt the clinician to consider endocarditis or CNS infection as etiologies of the focal neurological deficit.

Hyperglycemia is defined as blood glucose greater than 140 mg/dL. In both diabetic and nondiabetic patients, it has been associated with more severe stroke and worse neurologic outcome.20,21 The reasons for this are not entirely clear, but they may involve both metabolic effects of hyperglycemia and the effect of elevated glucose on the development of brain edema.22 MRI studies of hyperglycemic stroke patients have shown that elevated blood glucose promotes production of lactate in the brain and facilitates conversion of "at risk" tissue at the penumbra of the stroke into actual infarction.23 The emergency physician should therefore initiate insulin therapy if the blood glucose is above 185 mg/dL with the goal of achieving normoglycemia.24 

The issue of hypertension in acute stroke is a complex one. It certainly has been demonstrated that arterial hypertension is associated with worse prognosis in AIS.25,26,27 However, even without pharmacologic intervention, the blood pressure of these patients often will tend to lower spontaneously,28,29 and it is clear that precipitous falls in blood pressure can lead to worse neurological outcomes.30,31 Because of these complexities, the AHA guidelines for when to treat hypertension in stroke are set at relatively high blood pressures. In the patient who is a candidate for thrombolysis, blood pressure should not be treated unless greater than 185/110 mmHg. In this case, pharmacologic options for lowering blood pressure are included in the box on page 14. If one of these therapies does not lower the blood pressure appropriately, the patient should no longer be considered a candidate for rTPA. Patients who are not candidates for thrombolysis should not have blood pressure treated unless greater than 220/120 mmHg.

Although hypotension is rare in AIS, it has been associated with worse outcomes when below 100/70 mmHg.32 Hypotension should prompt the clinician to search for causes to explain both the neurologic deficit and the low blood pressure, including aortic dissection, hypovolemia, or decreased cardiac output from ischemia or dysrhythmia. Persistent hypotension should be treated with volume expansion with crystalloid and dysrhythmia management.33 

Patients with stroke should always be admitted to the hospital to a telemetry-monitored unit. Important measures such as carotid duplex ultrasound, echocardiography, and smoking cessation counseling are all more efficiently addressed in the inpatient setting.


The third European Cooperative Acute Stroke Study (ECASS III) trial investigated the use of rTPA in AIS up to 4.5 hours from the onset of symptoms.34 Like NINDS, this trial had as its primary end point an assessment of functional status at 90 days. The investigators found that administration of rTPA within 4.5 hours resulted in better functional outcomes but was associated with a higher risk of symptomatic ICH (2.4%, compared with 0.2% in the placebo group). Furthermore, this trial showed better outcomes in those treated earlier with rTPA. The ultimate conclusion suggested by the authors was that although patients outside the window of 3 hours may still benefit from thrombolysis, earlier therapy is still preferred.34  

The NINDS investigators were stroke experts, and questions exist as to whether the results of this group's findings could be extrapolated to the broad practice of community emergency medicine.35 This is still a controversial issue, although a large validation of the NINDS trial done in Europe specifically included half of its data from centers with little experience in thrombolysis and found similar functional outcomes and rates of ICH.36 Yet Dubinski and Lai cited higher in-hospital mortality (10.1%, compared with 5.8% in the untreated cohort) among patients treated with rTPA in the community than has been reported in prior studies.37  

Similar findings were reported in a German study (11.7% vs 4.5% in untreated), which further found that the risk of in-hospital mortality was higher in hospitals performing fewer than five thrombotic treatments per year.38 The implication for the community emergency physician is to reaffirm the importance of early neurologic consultation.

Emergency physician reluctance to use rTPA has been found to be the result both of questions about efficacy and concern for ICH.39 In the NINDS trial, the treatment arm had a symptomatic ICH risk of 6.4%. Even accounting for this higher risk of bleeding, those treated with rTPA had better functional outcomes. Subsequent studies have shown ICH risks similar to that found by the NINDS group.40  

A recent study in the Annals of Emergency Medicine found that out of a cohort of 33 malpractice litigation cases involving rTPA, 29 (88%) were initiated because of failure to treat with rTPA rather than for side effects of therapy.41 Given the potential for litigation, it is appropriate to have--and carefully document--an informed-consent-style discussion of risks and benefits with the patient/family when the patient is a candidate for treatment with rTPA.


AIS is a potentially devastating condition for which treatment is highly time-sensitive and infrequently administered. The emergency physician suspecting AIS should immediately rule out other causes of neurologic deficit, obtain prompt brain imaging, and consider the use of rTPA.

Given the complexity of issues surrounding the selection of appropriate candidates for thrombolysis and the conflicting data about its use in inexperienced centers, expert consultation should be considered mandatory in the care of AIS.


  1. Adams JG et al. Emergency Medicine. Acute Ischemic Stroke; 1072.
  2. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38:1655-711
  3. Adams JG, Chisolm CD. The Society for Academic Emergency Medicine Position on Optimizing Care of the Stroke Patient. Acad Emerg Med. 2003; 10: 805.
  4. Arora S, Broderick JP, Frankel M, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke. 2005;36:1232-1240.
  5. Adams JG et al. Emergency Medicine; 1073
  6. Smith Wade S, English Joey D, Johnston S. C, "Chapter 364. Cerebrovascular Diseases" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17th Edition
  7. Saver JL. Time Is Brain - Quantified. Stroke. 2006;37;263-6
  8. NINDS r-TPA Stroke Study Group. Tissue Plasminogen Activator for Acute Ischemic Stroke. NEJM. 1995;333:1581-7.
  9. Kerber KA, Brown DL, Lisabeth LD, et al. Stroke Among Patients with Dizziness, Vertigo, or Imbalance in the Emergency Department. Stroke. 2006;37:2484-7
  10. Van der Warp HB, Van Gijn J. Acute Ischemic Stoke. NEJM. 2007; 357:572-9.
  11. Seupaul RA, Worster A for the Best Evidence in Emergency Medicine Group. Is this patient having a stroke? Ann Emerg Med. 2009; 59: 120-2.
  12. Adams HP et al.
  13. Adams HP et al.
  14. Sagar G, Riley P, Vohrah A. Is admission chest radiography of any clinical value in acute stroke patients? Clin Radiol. 1996;51:499-502.
  15. Reith J, Jørgensen S, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet. 1996;347:422-5.
  16. Jorgensen HS, Reith J, Nakayama H, et al. What determines good recovery in patients with the most severe strokes? The Copenhagen Stroke Study. Stroke. 1999;30:2008-12.
  17. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet. 1996;347:422-5.
  18. Wang Y, Lim LL, Levi C, et al. Influence of admission body temperature on stroke mortality. Stroke. 2000;31:404-9.
  19. Adams JG et al. Emergency Medicine. Acute Ischemic Stroke. 1079
  20. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32:2426-32.
  21. Candelise L, Landi G, Orazio EN, Boccardi E. Prognostic significance of hyperglycemia in acute stroke. Arch Neurol. 1985;42:661-663.
  22. Lindsberg PJ, Roine RO. Hyperglycemia in acute stroke. Stroke. 2004;35:363-364.
  23. Parsons MW, Barber PA, Desmond PM, et al. Acute hyperglycemia adversely affects stroke outcome: a magnetic resonance imaging and spectroscopy study. Ann Neurol. 2002;52:20-8
  24. Adams HP et al.
  25. Willmot M, Leonardi-Bee J, Bath PM. High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension. 2004;43:18-24.
  26. Castillo J, Leira R, Garcia MM, et al. Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke. 2004;35:520-6.
  27. Vemmos KN, Spengos K, Tsivgoulis G, et al. Factors influencing acute blood pressure values in stroke subtypes. J Hum Hypertens. 2004;18:253-9.
  28. Phillips SJ. Pathophysiology and management of hypertension in acute ischemic stroke. Hypertension. 1994;23:131-6.
  29. Wallace JD, Levy LL. Blood pressure after stroke. JAMA. 1981;246:2177-80.
  30. Goldstein LB. Blood pressure management in patients with acute ischemic stroke. Hypertension. 2004;43:137-141.
  31. Johnston KC, Mayer SA. Blood pressure reduction in ischemic stroke: a two-edged sword? Neurology. 2003;61:1030-1.
  32. Castillo et al.
  33. Adams HP et al.
  34. Hacke W, et al. Thrombolysis Therapy with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. NEJM. 2008; 359:1317-29.
  35. Silbergleit R, Scott PA. Thrombolysis for Acute Stroke: The Incontrovertible, The Controvertible, and the Uncertain. Acad Emerg Med. 2005;12:348-50.
  36. Wahlgren M, et al for the SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275-82.
  37. Dubinsky R, Lai SM. Mortality of stroke patients treated with thrombolysis: Analysis of nationwide inpatient sample. Neurology. 2006;66:1742-4.
  38. Heuschmann PU, Berger K, Misselwitz B, et al., for the German Stroke Registers Study Group and for the Competence Net Stroke. Frequency of thrombolytic therapy in patients with acute ischemic stroke and the risk of in-hospital mortality. The German Stroke Registers Study Group. Stroke. 2003; 34:1106-13.
  39. Brown DL, Barsan WG, Lisabeth LD, et al. Survey of Emergency Physicians about Recombinant Tissue Plasminogen Activator for Stroke. Ann Emerg Med. 2005;46:56-60.
  40. Katzan IL, Hammer MD, Fulan AJ, et al. Quality Improvement and Tissue-Type Plasminogen Activator for Acute Ischemic Stroke. Stroke. 2003;34:799.
  41. Liang BA, Zivin JA. Empirical Characteristics of Litigation Involving Tissue Plasminogen Activator and Ischemic Stroke. Ann Emerg Med. 2008;52:160-4.


Dr. Aldeen is an assistant professor and the assistant residency director in the department of emergency medicine at Northwestern University Feinberg School of Medicine. Dr. Pirotte is a second-year resident in the department of emergency medicine at Northwestern University Feinberg School of Medicine. Medical Editor Dr. Robert C. Solomon is an attending emergency physician at Trinity Health System in Steubenville, Ohio, and clinical assistant professor of emergency medicine at the West Virginia School of Osteopathic Medicine.


In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards and American College of Emergency Physicians policy, contributors and editors must disclose to the program audience the existence of significant financial interests in or relationships with manufacturers of commercial products that might have a direct interest in the subject matter.

Dr. Aldeen, Dr. Pirotte, and Dr. Solomon have disclosed that they have no significant relationships with or financial interests in any commercial companies that pertain to this educational activity.

"Focus On: Acute Ischemic Stroke" has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME).

ACEP is accredited by the ACCME to provide continuing medical education for physicians. ACEP designates this educational activity for a maximum of one Category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he or she actually spent in the educational activity. "Focus On: Acute Ischemic Stroke" is approved by ACEP for one ACEP Category 1 credit.


ACEP makes every effort to ensure that contributors to College-sponsored programs are knowledgeable authorities in their fields. Participants are nevertheless advised that the statements and opinions expressed in this article are provided as guidelines and should not be construed as College policy. The material contained herein is not intended to establish policy, procedure, or a standard of care. The views expressed in this article are those of the contributors and not necessarily the opinion or recommendation of ACEP. The College disclaims any liability or responsibility for the consequences of any actions taken in reliance on those statements or opinions.


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