Brain Attack

Special Feature

By Saadia R. Akhtar, MD, MSc, Idaho Pulmonary Associates, Boise. Dr. Akhtar reports no financial relationship to this field of study. This article originally appeared in the March 2010 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD.

Each year, about 795,000 strokes occur in the United States; 85% of these are acute ischemic strokes. Acute stroke remains the third leading cause of death in the United States (137,000 persons yearly) and accounts for significant morbidity and disability in survivors. Risk factors for acute stroke include race (incidence is higher in African-American and Hispanic patients, compared to Caucasians), age (75% of patients are > 65 years), obesity, hypertension, atrial fibrillation, diabetes, hyperlipidemia, and tobacco use.1

The underlying pathophysiology of acute ischemic stroke generally involves acute intracranial arterial occlusion (thrombotic or embolic). Neurons in the area of the brain being primarily supplied by the occluded vessel die within minutes. Adjacent to and surrounding the immediate area of ischemia and infarct are further at-risk areas of diminished blood flow, the ischemic penumbra. Without rapid revascularization, these areas may infarct as well, greatly extending the injury.2

In the past, clinical observation and supportive care were all that could be offered for acute ischemic stroke. More recently, thrombolysis in the early hours has been shown to significantly improve outcomes. To convey the importance of early detection and intervention for stroke, the term "brain attack" (analogous to heart attack) has been advocated by some experts. This review will discuss diagnosis and initial evaluation of acute ischemic stroke, the evidence and indications for thrombolysis, and some key issues in subsequent ICU management.

Diagnosis

Acute ischemic stroke typically presents as acute onset of focal neurological deficits with or without higher cerebral dysfunction. As the term brain attack implies, these patients should be triaged with no less urgency than those with acute myocardial infarction. After assessing and stabilizing airway, breathing, and circulation, a focused history (including risk factors for ischemic stroke and potential contraindications for thrombolytics, discussed below) and examination should be performed. Determination of the exact time of symptom onset is essential for making treatment decisions.3 It is important to consider and rule out conditions that may mimic stroke, such as severe hypoglycemia, seizure, migraine, or conversion disorder.4 Use of a formal stroke scale is recommended by expert guidelines. There are a variety of validated assessment and scoring systems for initial diagnosis, grading of severity and subsequent monitoring of patients with acute stroke. The National Institutes of Health Stroke Scale (NIHSS) is perhaps the most commonly endorsed and utilized. It is a simple series of tests evaluating level of consciousness, comprehension, and visual, motor, sensory, and language responses, taking about 5 minutes to administer.5

The initial imaging study should be a noncontrast head CT scan. This will generally rule out hemorrhagic stroke, as well as mass lesions, and may give clues about the vascular distribution of an ischemic stroke. A standard brain MRI is equally useful but generally not as readily available in many centers.6

Additional imaging may be obtained but is not usually necessary in the initial evaluation and decision-making process about thrombolytic therapy. CT-angiography or contrast-enhanced MR-angiography can define vascular anatomy and directly identify vascular occlusions or stenoses. Diffusion-weighted MRI will demonstrate infarct within minutes of vascular occlusion and perfusion CT or perfusion-weighted MRI may help to delineate the ischemic penumbra.6

Thrombolysis

Stroke management changed dramatically in 1995. The National Institute of Neurological Disorders and Stroke (NINDS) undertook a randomized, double-blind, placebo-controlled clinical trial of the use of intravenous (IV) recombinant tissue plasminogen activator (tPA; 0.9 mg/kg with maximum dose of 90 mg) within 3 hours of stroke onset on neurological outcome at 3 months. Several important exclusion criteria were used: history of intracranial hemorrhage, stroke or head trauma in the past 3 months, major surgery in the past 2 weeks, GI or GU hemorrhage in the past 3 weeks, arterial puncture at noncompressible site within the past week, current use of anticoagulants or evidence of coagulopathy, BP > 185/110 mm Hg, minor or rapidly improving symptoms, symptoms strongly suggestive of subarachnoid hemorrhage, or seizure at onset of stroke. The study found that, compared with placebo, patients receiving tPA had an increase in favorable outcome; they were at least 30% more likely to have minimal or no disability at 3 months following their strokes (this benefit was later shown to extend to 1 year following treatment). This was despite an increase in symptomatic intracerebral hemorrhage in the first 36 hours following tPA administration (6.4% vs 0.6% in the placebo group). There were no differences in serious systemic hemorrhage or in 3-month mortality between the placebo and treatment groups.7

The findings of the NINDS trial have subsequently been replicated in large prospective observational studies of tPA.6 More recent, robust data by Hacke et al support extension of tPA use to 4.5 hours after stroke onset, although there is a clear direct relationship between earlier time of treatment and likelihood of favorable outcome.8 Systemic tPA is now the standard of care for acute ischemic stroke, and it is suggested that institutions develop their own protocol for this with inclusion and exclusion criteria based on those used in the above hallmark studies.4

There is no place in acute stroke management for other thrombolytic agents at this time: Considerably higher incidence of intracerebral hemorrhage has been seen with streptokinase and data for other agents (urokinase, desmoteplase) are insufficient.4

The role of intra-arterial thrombolysis directly at the occlusion site remains unclear. There is limited evidence to suggest benefit in patients with middle cerebral artery occlusions presenting within 6 hours of stroke onset, but no studies directly compare systemic IV tPA to intra-arterial thrombolysis.9 There are some pilot studies looking at intra-arterial thrombolysis as an early "rescue" therapy if response to systemic IV tPA is limited.6

Finally, at this time, there is no defined role for mechanical thrombectomy/embolectomy in management of acute ischemic stroke. Small studies of endovascular devices have shown reasonable rates of vascular recanalization, but neurologic outcome has not been evaluated as a primary endpoint, and there have been no head-to-head comparisons with IV tPA.10

ICU Care

Airway, ventilation, and oxygenation must continue to be monitored closely once a patient is admitted to an ICU. Depressed level of consciousness and brainstem dysfunction from stroke may lead to hypoventilation, hypoxia, airway compromise, or aspiration; a low threshold must be maintained for intubation in such patients. Untreated hypoxia may worsen cerebral ischemic injury. Aspiration and other pneumonia may adversely impact outcomes. If intubation and mechanical ventilatory support are required, prognosis is guarded; half or more of patients requiring intubation in the setting of acute stroke may not survive beyond 30 days.11

Blood pressure management is one of the key aspects of acute stroke care in the ICU. Hypertension is common after acute stroke, and may reflect underlying chronic hypertension or acute pain or anxiety. It may also be an appropriate physiological response to maintain cerebral perfusion in the setting of loss of normal autoregulation at the area of ischemia. There is a clear U-shaped relationship between initial blood pressure and mortality from acute stroke, with adverse outcomes associated with very low and very high systolic blood pressures.12 Very severe hypertension may increase risk of cerebral edema, hemorrhagic transformation of the ischemic stroke, or other end-organ complications (myocardial ischemia, pulmonary edema, acute renal failure); overly aggressive lowering of blood pressure may worsen cerebral perfusion and risk extension of an ischemic stroke.6

Therefore, current guidelines suggest not treating blood pressure in the setting of acute ischemic stroke until it exceeds 220/120 mm Hg; if patients have received thrombolytics, this parameter is lowered to 180/105 mm Hg. Beyond this, blood pressure should not be lowered more than about 15% in the first day.4 The antihypertensive agents of choice include nonselective beta-blockers, such as labetolol, and calcium channel blockers, such as nicardipine and ACE-inhibitors; nitroprusside and hydralazine should be avoided as they may be more likely to cause cerebral vasodilation and elevation of intracranial pressure.6

Hypotension is uncommon in the setting of acute ischemic stroke and is a poor prognostic indicator. Intravascular volume should be maintained in these patients, using isotonic IV fluids. Clinical trials are ongoing to assess whether inducing hypertension may have benefit in patients with acute ischemic stroke and initial hypotension.6

It remains unclear how to best manage body temperature in patients with acute ischemic stroke. Hyperthermia (fever) is associated with worse neurological outcomes, but it has been difficult to demonstrate improvement in outcomes with treatment (or prophylaxis) with antipyretics.13,14 Thus, the only recommendation that can be made is to consider antipyretics if fever occurs and treat the source of fever whenever possible. Similarly, although hypothermia is neuroprotective in animal models of stroke and has been shown to improve neurological outcomes after out-of-hospital cardiac arrest, further clinical trials are needed to determine whether it may benefit patients with acute ischemic stroke.15,16

Hyperglycemia is associated with poorer outcomes after acute ischemic stroke. It is clearly a marker of stroke severity. It worsens ischemic damage in animal models of acute stroke and is associated with increased risk of hemorrhagic transformation of acute stroke, greater infarct size on MRI, and, in some reports, less favorable neurological outcome and increased mortality. The mechanism is unclear; anaerobic glycolysis, increased free-radical formation, and disruption of the blood-brain barrier may occur. Despite these observations, there is a paucity of data to guide how best to manage glucose and whether any approach alters outcomes in patients with acute ischemic stroke. Until further evidence is obtained, guidelines recommend targeting glucose < 140-180 mg/dL.4

Early antiplatelet therapy with aspirin is indicated for all patients with acute ischemic stroke. Two very large randomized, placebo-controlled clinical trials (about 20,000 patients each) have shown that aspirin given within 48 hours of acute ischemic stroke reduces risk of recurrent stroke, death, and dependence.17,18 It is recommended that aspirin be started immediately if thrombolytics are not given; if IV tPA is given, aspirin should be started 24 hours later.19

Finally, ICU caregivers must be vigilant for neurological complications of acute ischemic stroke: cerebral edema, hemorrhagic transformation, and seizure. Frequent examinations and monitoring with a validated stroke scale are essential for identifying neurological changes early. Cerebral edema is most common following large middle cerebral artery distribution or cerebellar strokes. Although it can progress rapidly with severe clinical deterioration within the first 24 hours, it presents most typically at about day 4. Usual treatment for elevated intracranial pressure is recommended (elevation of head of bed, hyperosmolar therapy, short-term moderate hyperventilation, CSF drainage) along with early consideration of decompressive craniotomy. Hemorrhage at the area of stroke is often limited, of little clinical consequence, and managed supportively. For more significant, symptomatic intracranial hemorrhage, particularly after tPA, fresh frozen plasma and cryoprecipitate should be administered emergently.4,6

Conclusion

Acute ischemic stroke is a common problem resulting in considerable morbidity and mortality. Rapid, coordinated triage/evaluation, early treatment with thrombolytics, and subsequent aggressive supportive ICU care have the potential to vastly improve outcomes.

References

1. Stroke Facts. Available at: www.cdc.gov/stroke/facts.htm. Accessed Feb. 2, 2010.

2. Fulgham JR, et al. Management of acute ischemic stroke. Mayo Clin Proc. 2004;79:1459-1469.

3. Yew KS, Cheng K. Acute stroke diagnosis. Am Fam Physician. 2009;80:33-40.

4. Adams HP Jr, et al. Guidelines for the early management of adults with ischemic stroke. Stroke. 2009;38:1655-1711.

5. Stroke Scales and Clinical Assessment Tools. Available at: www.strokecenter.org/trials/scales. Accessed Feb. 2, 2010.

6. Finley Caulfield A, Wijman CA. Critical care of acute ischemic stroke. Crit Care Clin. 2007;22:581-606.

7. 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;333:1581-1587.

8. Hacke W, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329.

9. Furlan A, et al. Intra-arterial prourokinase for acute ischemic stroke. JAMA. 1999;282:2003-2011.

10. Smith WS, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke. Stroke. 2005;36:1432-1438.

11. Bushnell CD, et al. Survival and outcome after endotracheal intubation for acute stroke. Neurology. 1999;52:1374-1381.

12. Leonardi-Bee J, et al. Blood pressure and clinical outcomes in the International Stroke Trial. Stroke. 2002;33:1315-1320.

13. Saini M, et al. Effect of hyperthermia on prognosis after acute ischemic stroke. Stroke. 2009;40:3051-3059.

14. Badjatia N. Hyperthermia and fever control in brain injury. Crit Care Med. 2009;37:S250-S257.

15. Den Hertog HM, et al. Cooling therapy for acute stroke. Cochrane Database Syst Rev. 2009;1:CD001247.

16. Linares G, Mayer SA. Hypothermia for the treatment of ischemic and hemorrhagic stroke. Crit Care Med. 2009;37:S243-S249.

17. CAST: Randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997;349:1641-1649.

18. The International Stroke Trial (IST): A randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349:1569-1581.

19. Sandercock P, et al. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2003;2:CD000029.