Emergency Setting

Stroke remains a clinical diagnosis; therefore history and physical examination are critical. Given the narrow therapeutic window for acute treatment, timely diagnosis and identification of symptom onset are essential. Approximately 1 to 2 million neurons are lost per minute of delay. Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) (alteplase [Activase]) is the only medication approved by the U.S. Food and Drug Administration for the treatment of AIS. The randomized multicenter National Institute of Neurological Disorders and Strokes (NINDS) rt-PA study demonstrated roughly double the odds of a very favorable outcome in patients who were treated with rt-PA within 3 hours of symptom onset compared with placebo. This benefit was observed at 3 months in the primary outcome of a composite of the National Institutes of Health (NIH) Stroke Scale (NIHSS), modified Rankin Scale (mRS), Barthel Index, and Glasgow Outcome Scale. Subsequent randomized trials, including Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS), European Cooperative Acute Stroke Study (ECASS), and ECASSII, failed to show benefit for thrombolysis in the 3- to 6-hour time window. ESCASS III, however, identified a significant but slightly smaller benefit in patients treated with rt-PA between 3 and 4.5 hours of symptom onset (mRS 0 to 1 in 52.4% treatment arm vs. placebo 45.2%). A recent meta-analysis of 27 randomized trials (n = 10,187) reviewing thrombolysis in AIS showed that thrombolysis (IV and intraarterial) up to 6 hours after AIS significantly reduced morbidity and mortality at 3 to 6 months (odds ratio [OR] 0.85; confidence interval [CI], 0.78 to 0.93) and that treatment within 3 hours was associated with more benefit (OR, 0.66; 95% CI, 0.56 to 0.79).

The major contraindications to IV rt-PA include major surgery within the past 14 days, international normalized ratio (INR) greater than 1.7, platelet count less than 100,000, history of intracerebral hemorrhage, and sustained blood pressure greater than 185/110 mm Hg. The American Heart Association/American Stroke Association (AHA/ASA) recommends administration of IV rt-PA (0.9 mg/kg with 10% given as a bolus and the remainder as an infusion over 1 hour) to eligible patients within 4.5 hours of stroke symptom onset and a door-to-needle time of less than 60 minutes. Many centers have adopted an approach that was developed in Helsinki, Finland, in which suspected acute stroke patients are taken directly from the door to the computed tomography (CT) scanner and, if eligible, are given IV rt-PA immediately after the CT scan, reducing door-to-needle time to about 20 minutes.

Given worse outcomes in patients ineligible for IV rt-PA, especially for those with middle cerebral artery (MCA) occlusions, intra-arterial rt-PA has been evaluated for safety and efficacy. The Prolyse in Acute Cerebral Thromboembolism (PROACT) study randomized 40 patients to intra-arterial infusion of prourokinase or placebo. The treatment arm was associated with a significant increase in vessel recanalization; however, there was a concomitant increase in symptomatic intracerebral hemorrhage (sICH) (15.4% vs. 7.1%). PROACT II, a multicenter single blind trial in which 180 patients were randomized to treatment with intra-arterial prourokinase plus heparin or heparin alone demonstrated improved outcome at 90 days for patients with stroke due to MCA occlusion who were treated with prourokinase within 6 hours of symptom onset. The primary endpoint of mRS 0 to 2 was achieved in 40% of the treatment arm and 25% in the control group, with a 66% recanalization rate in the treatment group versus 18% in the control group. There was an increase in early sICH in the treatment arm (10% vs. 2%). This study opened the window for intervention for AIS to up to 6 hours with intra-arterial thrombolysis.

Nonpharmacologic approaches to thrombolytic therapy have also been developed. Four devices are available in the United States: the MERCI retriever, the Penumbra suction catheter, the Solitaire stentriever, and the Trevo retrieval system. Each has been shown to successfully open thrombosed arteries, but none has been subjected to a randomized comparison to placebo or IV tissue plasminogen activator (tPA). The one randomized clinical trial (RCT) in this arena compared the MERCI with Solitaire devices and found improved recanalization rates and clinical outcomes with the Solitaire stentriever.

The combination of IV and endovascular thrombolytic therapy has also been studied. The Interventional Management of Acute Stroke (IMS) series of trials evaluated the feasibility and safety of combining IV rt-PA and intra-arterial thrombolysis. Ultimately the IMS III randomized trial of standard IV rt-PA versus IV rt-PA followed by intra-arterial thrombolysis was stopped early because of futility after more than 650 patients were randomized. There was no significant difference in functional outcome (mRS of 2 or less) at 90 days (40.8% with endovascular therapy, 38.7% with IV rt-PA). On the basis of these data, the AHA/ASA suggested that it is reasonable to consider endovascular thrombolytic therapy in patients who are not candidates for IV rt-PA or for patients with a proximal MCA occlusion who are at an experienced stroke center with qualified interventionalists. Evidence does not support substitution of intra-arterial thrombolysis for IV rt-PA.

There is emerging evidence to support the use of therapeutic protocols that combine rt-PA and intra-arterial stenting. The EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-arterial) study, based in Australia and New Zealand, randomized patients already receiving rt-PA (0.9 mg/kg) for AIS, within 4.5 hours of onset, to endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving IV rt-PA alone. The study was limited to patients with strokes in specified locations (internal carotid and middle cerebral arteries) and who had clearly salvageable brain tissue: the ischemic core had to be less than 70 mL on CT perfusion imaging.

Only 70 patients were enrolled in the trial before it was stopped because of significant outcome benefits in the intervention (stent) group. There were two observable benefits. First, the proportion of ischemic tissue that was reperfused was significantly greater in the endovascular-therapy group than in the rt-PA–only group (median, 100% vs. 37%; P < .001). In addition, there were significant neurologic improvements at 3 and 90 days. There were no significant differences in death or intracranial hemorrhage. Endovascular therapy was initiated at a median of 210 minutes after the onset of stroke symptoms.

A Dutch multicenter study, MR CLEAN (Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands), randomized patients with proximal arterial occlusion (distal intracranial carotid artery, middle cerebral artery [M1 or M2], or anterior cerebral artery [A1 or A2]), in the anterior cerebral circulation, within 6 hours of symptom onset, 89% of whom were receiving rt-PA, to intra-arterial therapy—intra-arterial rt-PA or endovascular stenting, or standard therapy—the majority of whom received continued IV thrombolysis. Five hundred patients were enrolled at 16 centers, and 190 of 223 patients randomized to the “intra-arterial” group received endovascular stents. There was significant improvement in functional outcome at 90 days in the intervention group, as measured by the modified Rankin Score (0 to 2) (32.6% vs. 19.1%; OR, 1.67; CI, 1.21 to 2.30; absolute risk reduction [ARR], 13.5%; number needed to treat [NNT], 8). There were no significant differences in mortality or intracranial hemorrhage.

The ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke) trial was a large, international, 22-center trial that randomized a similar cohort of patients with proximal intracranial occlusion in the anterior circulation but stretched the time limit to 12 hours after symptoms had become apparent. Of the 316 participants enrolled, 238 received IV alteplase, and of those, 120 received endovascular stenting. Again, the study was stopped early for efficacy; mortality was significantly reduced in the group who received endovascular stents (10.4% vs. 19.0% in the control group; P = .04; ARR, 8.6%; NNT, 12). The intervention group also had significantly better functional outcomes at 90 days (53.0% vs. 29.3% in the control group; P < .001; ARR, 23.7%; NNT, <5). There was no difference in the development of intracranial hemorrhage (3.6% vs. 2.7%, control group; P = .75).

In summary, endovascular stenting appears to be a highly effective therapy for patients suitable for thrombolysis who have proximal anterior circulation or middle cerebral strokes, small infarct cores, reasonably good collateral circulation, and rapid access to an interventional neuroradiology unit.

Critical Care Management

Blood Pressure Control and Cardiac Care

High blood pressure after AIS occurs in up to 80% of patients. The ideal blood pressure after AIS is unknown; however, both high and low blood pressures are associated with poor outcome. Ideally, blood pressure should be monitored continuously by an intra-arterial catheter to detect rapid fluctuations. High blood pressure is associated with an increased risk of recurrent AIS within 14 days; patients in whom systolic blood pressure (SBP) is more than 200 mm Hg have a 50% or more greater risk of recurrence compared with patients in whom SBP is 130 mm Hg. There is a U-shaped relationship between blood pressure and mortality. A post hoc analysis of data from the International Stroke Trial (IST) suggests that for every 10 mm Hg below 150 mm Hg the risk of early death increases by nearly 18%, and for every 10 mm Hg above 150 mm Hg early death increases by 3.8%. A smaller observational study suggested that for every 10 mm Hg below 180 mm Hg of SBP, the risk of early poor outcome increased by 25%, whereas for every 10 mm Hg above 180 mm Hg, the risk of poor outcome increased by 23%. It is presumed that hypertension is associated with poor outcome because of increased risk of recurrent stroke, hemorrhagic conversion of ischemic infarct, continued vascular damage, and worsening of cerebral edema.

Although hypertension is associated with poorer outcome, the impact of lowering blood pressure is unclear. The angiotensin-receptor blocker candesartan for treatment of acute stroke trial (SCAST) randomized more than 2000 patients to an angiotensin-receptor blocker (candesartan) or a placebo for 1 week after stroke. At 6 months the treatment group had a significantly lower blood pressure but also a higher risk of poor functional outcome as measured by the mRS (OR, 1.17). Current recommendations from the AHA/ASA include permissive hypertension for patients who did not receive thrombolytic therapy (SBP <220 mm Hg; diastolic blood pressure [DBP], < 120 mm Hg). For patients who are to be treated with rt-PA, blood pressure should be maintained below 185/110 mm Hg before drug administration and below 180/105 mm Hg for the first 24 hours after treatment. In most patients, blood pressure declines without any medical intervention. If antihypertensive therapy is needed, then the drug of choice should be short acting and have a reliable dose-response curve. Although labetalol and nicardipine are commonly used in the ICU, there are no data to guide choice of optimal antihypertensive agents.

Frank hypotension is relatively uncommon in stroke patients and should be avoided. Patients who have hypotension should be evaluated for myocardial ischemia and for aortic dissection, which may be causally related to the stroke. Neurogenic myocardial stunning may result from the stroke and may result in cardiogenic shock. Between 10% and 18% of patients with AIS have an elevated serum troponin level. Patients who become hypotensive after thrombolytic therapy should be promptly evaluated for extracranial hemorrhage and for cardiac tamponade from hemopericardium.

Pharmacologic augmentation of blood pressure in patients who are normotensive (induced hypertension) is not routinely recommended. Theoretically, induced hypertension might increase cerebral blood flow to ischemic regions of brain. Small pilot studies suggest that raising blood pressure with vasopressors might be safe, but its impact on outcome is not known.

Fluid Management

Stroke patients can become volume depleted from insensible losses and decreased oral intake from dysphagia and altered mental status. Euvolemia should be maintained in all patients. IV fluids should be dosed and adjusted daily based on clinical determination of volume status. There is no evidence to support routine placement of a central venous catheter to guide volume administration by measurement of central venous pressure. Isotonic crystalloid IV fluid solutions, such as 0.9% saline, Normosol-R, or Plasma Lyte 148, are preferred. Hypotonic solutions increase cerebral edema and exacerbate brain injury. Hypertonic solutions have not been proven to be beneficial. A large randomized double-blinded trial found no benefit to administration of 25% albumin compared with normal saline with respect to 90-day outcome.

Glucose Control

Hyperglycemia is present in up to one third of AIS patients and in observational studies is independently associated with poor outcomes. Whether hyperglycemia is a marker of injury severity or is causally related to brain injury, or both, remains unclear. Deleterious effects of hyperglycemia might include increased brain tissue acidosis, increased blood–brain barrier permeability, and increased odds of hemorrhagic transformation. Persistent hyperglycemia (>200 mg/dL) within the first 24 hours after stroke correlates with expansion of stroke volume and poor neurologic outcome. The optimal blood glucose level is unknown, and treatment targets vary across guidelines. In the Intensive Insulin Therapy Trial (ITT), AIS patients were randomized to receive intensive insulin infusion (<126 mg/dL) versus standard subcutaneous insulin treatment for 24 hours. Intensive insulin therapy was associated with better glucose control over the first 24 hours but also with increased infarct size on magnetic resonance imaging. A 2014 Cochrane review analyzed 1583 patients from 11 RCTs and suggested that intensive insulin therapy was associated with an increased risk of symptomatic hypoglycemia and did not affect functional outcome or mortality. The Stroke Hyperglycemia Insulin Network Effort (SHINE) trial is an ongoing multicentered, randomized double-blinded trial that aims to compare aggressive glycemic control with IV insulin to maintain blood glucose in the range of 80 to 130 mg/dL versus “routine” glycemic control with subcutaneous insulin to a target of below 180 mg/dL. Current AHA/ASA guidelines recommend maintenance of glucose between 140 and 180 mg/dL (7 to 10 mmol/L) and use of an insulin infusion if needed. Frequent monitoring of blood glucose levels should be performed, and hyperglycemia should be minimized.

Hypoglycemia is a potential mimic of AIS, and serum glucose levels should be checked in the emergency setting. Hypoglycemia after AIS is uncommon and is typically related to diabetic medications. Hypoglycemia (glucose level <60 mg/dL [3.3 mmol/L]) should be identified and treated rapidly.

Temperature

Fever occurs in 25% to 50% of patients with AIS and is consistently and independently associated with increased morbidity and mortality in cohort studies. Fever on admission and within the first 24 hours after stroke onset is associated with worse outcome. For each 1° C increase in admission body temperature, the relative risk of poor outcome increases by 2.2. Fever may be due to a systemic inflammatory response, but an infectious cause should be sought.

Although fever control is recommended as standard of care, there have been no randomized trials of fever control. Trials have, however, examined fever prevention. In the Paracetamol (Acetaminophen) in Stroke (PAIS) trial, patients with admission temperature (36° C to 39° C) were randomized to paracetamol (6 g) or placebo within 12 hours of stroke onset. There was no difference between groups in outcome (mRS) at 3 months. A post hoc analysis identified a modest increase in functional improvement in patients with baseline temperature higher than 37° C. To corroborate these results, a PAIS II trial is currently ongoing.

Patients who have hypothermia may have reduced mortality and better long-term outcomes. The impact of therapeutic hypothermia on outcome is unknown. Two clinical trials have shown feasibility of both surface and endovascular cooling methods in patients with AIS. The Intravascular Cooling in the Treatment of Stroke (ICTuS-L) trial suggested that the combination of hypothermia (induced by an endovascular cooling catheter) and thrombolysis is feasible. Hypothermia was not associated with an increased risk of bleeding; however, there was an association with pneumonia. The ongoing ICTuS 2/3 study aims to further test the safety of hypothermia and the difference in outcome between patients treated with hypothermia plus thrombolysis and patients treated with thrombolysis alone. An international multicenter phase III clinical trial is also underway to determine whether hypothermia improves functional outcome after AIS.

Hemoglobin Management

Both anemia and polycythemia may be deleterious in patients with AIS. A prospective cohort study of more than 800 AIS patients showed an association between anemia and increased mortality, and the worst outcomes present in those with both low and high hemoglobin levels (i.e., a “U-shaped” relationship between hemoglobin and outcome). A retrospective analysis of 109 patients with AIS showed that low hemoglobin count and red blood cell transfusion was associated with prolonged NICU stay and duration of mechanical ventilation but was not associated with mortality or 3-month functional outcome. In this study nearly all patients (97.2%) had anemia, and one third received blood transfusions (at the discretion of the physician), which did not confer an advantage in long-term outcome.

The impact of red blood cell transfusion on outcome is unclear, and no prospective randomized trials have addressed the optimal transfusion threshold in patients with AIS. In the general critical care population, a meta-analysis demonstrated an increased risk of health-care–associated infections, such as pneumonia and sepsis, with a liberal transfusion policy (hemoglobin count <10 g/dL) compared with a restrictive policy (hemoglobin count <7 g/dL). A second meta-analysis showed that restrictive blood transfusion (hemoglobin count <7 g/dL) was associated with a decreased incidence of coronary events, bacterial infections, and mortality.

In patients with AIS, the risks associated with both anemia and red blood cell transfusion should be weighed on an individual basis. It is recommended that both anemia and aggressive transfusion practice be avoided.

Antithrombotic Medications

For patients who are not candidates for reperfusion therapy, antithrombotic therapy is the mainstay of treatment. The Chinese Acute Stroke Trial (CAST), a randomized placebo-controlled trial of more than 20,000 patients, and the International Stroke Trial (IST), a randomized trial of almost 20,000 patients, demonstrated a decrease in ischemic stroke recurrence rate when aspirin was given within 48 hours of symptom onset (1.6% vs. 2.1%; P = .01; and 2.8% vs. 3.9%; P < .001, respectively), with no significant increase in hemorrhagic conversion. In the CAST study, there was also a small but significant decrease in mortality in aspirin-treated patients (3.3% vs. 3.9%). Treatment effect was independent of age, stroke severity, and stroke subtype.

More recent studies corroborate the benefit of early antithrombotic drug administration in patients with AIS. In the Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence (FASTER) trial, almost 400 patients with transient ischemic attack (TIA) or stroke (NIHSS <4) were randomized to treatment with clopidogrel or placebo and simvastatin or placebo. All patients also received aspirin. The clopidogrel arm had a 7.1% stroke risk within 90 days compared with 10.8% in the placebo arm (risk ratio, 0.7 [95% CI, 0.3 to 1.2]; ARR, 3.8% [95% CI, 9.4 to 1.9]; P = .19). In the randomized, double-blinded placebo controlled Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial, 5170 Chinese patients were assigned to clopidogrel and aspirin or to placebo plus aspirin within 24 hours of minor stroke or TIA. The primary endpoint, stroke at 90 days, occurred in 8.2% of patients in the clopidogrel-aspirin group and in 11.7% of the aspirin-alone group (hazard ratio, 0.68; 95% CI, 0.57 to 0.81; P <.001). There was no difference in hemorrhage rate (0.3%). An ongoing randomized, double-blinded, placebo-controlled study in the United States, the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, is assessing the impact on outcome (ischemic vascular event at 90 days) of clopidogrel and aspirin initiated within 12 hours of symptom onset. Additional antiplatelet agents are also being studied. The Acute Stroke of Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial is an ongoing double-blinded RCT that aims to compare the effect on outcome of ticagrelor versus aspirin.

Currently, most patients with AIS should be treated with aspirin 325 mg within 24 to 48 hours after stroke symptom onset. The primary effect of aspirin is a reduction in early recurrent stroke. Aspirin is not recommended as a substitute for rt-PA. For patients who receive thrombolysis, antithrombotic agents must be avoided for the first 24 hours. Aspirin is usually initiated after a head CT obtained 24 hours after rt-PA administration demonstrates absence of intracerebral hemorrhage. There is no convincing evidence to support the use of other oral antiplatelet agents such as clopidogrel, dipyridamole, ticagrelor, and ticlopidine. Administration of IV antiplatelet agents, such as the glycoprotein IIb/IIIa inhibitor (abcixamab), is largely ineffective.

Data do not support the routine use of systemic anticoagulation with heparin in AIS. Therapeutic heparin may be considered in select patients with carotid artery dissection, although there are no randomized clinical trials to support this practice. The decision about whether to use systemic anticoagulation in the acute to subacute period should be made on a case-by-case basis. A detailed discussion is beyond the scope of this chapter.

Malignant Infarction

Malignant infarction refers to life-threatening cerebral edema from AIS. It is observed in 1% to 10% of patients with supratentorial infarction and typically in patients with occlusion of the internal carotid artery or proximal MCA ( Fig. 64-1 ). Peak swelling usually occurs 2 to 5 days after stroke onset, but up to one third of patients may have neurologic deterioration in the first 24 hours. Clinical features of malignant infarction include headache, declining level of consciousness, nausea/vomiting, paralysis ipsilateral to the hemispheric infarction, and signs of brainstem dysfunction. The prognosis of malignant infarctions is poor, with mortality of up to 80% in malignant MCA infarction. In a retrospective case-controlled study, predictors of malignant infarction included early hypodensity involving more than 50% of the MCA territory, a history of hypertension or heart failure, increased baseline white blood cell count, and involvement of additional vascular territories. An autopsy series of 192 patients identified 45 patients with nonlacunar malignant MCA territory strokes, and predictors of malignant edema included younger age, no history of stroke, carotid occlusion, higher heart weight, and abnormal ipsilateral circle of Willis, with a slight predominance of female sex.

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