Guidelines for the Early Management of Adults With Ischemic Stroke

A. EMS Assessment

EMS assessment begins with the initial 9-1-1 contact (Table 2). The role of the dispatch system is to ensure immediate triage and dispatch of appropriate EMS providers when acute stroke is suspected by either the caller or the dispatcher.²³ Data from 2 systems indicate that dispatchers correctly suspected or identified 52% of patients ultimately proven to have had a stroke on initial telephone evaluation.^7,24 These data imply that educational programs should be aimed at dispatchers to increase their awareness of stroke symptoms. Stroke should be given a priority dispatch similar to that for acute myocardial infarction or trauma.²⁵

After ambulance arrival on the scene, EMS providers should obtain a focused history and patient assessment, provide necessary stabilization and treatment, and transport immediately to the closest, most appropriate facility (Table 3). The word appropriate is key because it means that an ambulance may bypass a hospital that does not have the resources or institutional commitment to treat patients with stroke if a more appropriate hospital is available within a reasonable transport interval. Advance notice to the receiving emergency department (ED) of the impending arrival of a potential stroke patient, along with information on comorbid conditions and estimated time of symptom onset, will speed the subsequent ED assessment.

Critical elements of the patient’s history must include information on time of symptom onset (Table 4). This may require obtaining information from bystanders or, preferably, transporting witnesses with the patient. Similarly, next of kin, if available, may be needed for information or consent and should travel to the receiving hospital concurrently. Telephone numbers, including cellular telephone numbers, of witnesses or relatives may help the ED to clarify the history or seek consent for treatment. A list of the patient’s medications, or the medication containers themselves, should be sought, with particular attention paid to identifying anticoagulant (both oral and injectable), antiplatelet, and antihypertensive drug use.

After the patient’s airway, breathing, and circulation (ABCs) are assessed and stabilized, common presenting signs of stroke should be sought and a focused examination completed. Prehospital stroke assessment tools have proved effective in identifying stroke patients in the field. The Los Angeles Prehospital Stroke Screen uses patient history, physical findings, and finger stick glucose determination to identify stroke patients.²⁶ The Cincinnati Prehospital Stroke Scale is an alternative instrument with fewer data elements (Table 5), requiring only 30 to 60 seconds to complete.²⁷ Other prehospital stroke evaluation tools exist, although data on their validity are limited.

B. EMS Management

Guidelines for EMS management are presented in Table 3.^25,28 After initial stabilization, it is recommended that patient transport commence as soon as possible, with cardiac monitoring and intravenous access established during transport, if possible. Isotonic crystalloids (most commonly normal saline solution) are recommended for resuscitation, if needed. Dextrose-containing fluids should be avoided unless hypoglycemia is present or strongly suspected because excessive glucose may be injurious to stroke patients. No recommendations can be offered on the prehospital management of hypertension in patients with suspected stroke, and intervention is best accomplished after hospital arrival.

It is well recognized that hypoglycemic patients may have symptoms that mimic an acute stroke, manifesting focal symptoms, altered speech, and/or cognitive changes, and therefore EMS assessment of blood glucose has been a routine practice for many years. A single report suggests that a more selective approach may be possible, with blood glucose measurement advocated only in the presence of a history suspicious for hypoglycemia or inability to obtain adequate patient information.²⁹ That study is limited, however, by its retrospective methodology and an upper confidence interval of 2.4% for the likelihood of failing to identify a hypoglycemic patient. At present, checking blood glucose concentrations in most patients with stroke is a prudent step, even among patients without a history of diabetes mellitus or use of insulin.

The availability of resources to care for patients with acute stroke varies widely both among and within communities. The National Institutes of Health (NIH) Task Force report, “Improving the Chain of Recovery for Acute Stroke in Your Community,” recommends identifying hospitals capable of providing acute stroke care and creating a transport system to these centers based on patient location. Such systems require advanced planning and frequent updating and should incorporate EMS representatives, community leaders, hospitals, and physicians to ensure clear guidance for EMS providers with regard to patient destination.

Identification of an effective neuroprotective therapy may further expand the role of EMS in the treatment of acute stroke. The feasibility of initiation of hypothermia has also been demonstrated in the prehospital setting.³⁰ Of importance for future research is the fact that it appears possible to incorporate EMS into the research process, with EMS personnel having demonstrated success in facilitating physician cell phone elicitation of consent from patients and in delivering experimental stroke therapy.^31,32

C. Air Medical Transport

Air medical (helicopter) transport for patients with acute stroke appears beneficial, although the data are limited. Helicopters may extend the range of thrombolytic therapy to rural areas.³³ They could deliver teams to administer tPA and subsequently transfer treated patients,³⁴ expand enrollment for acute stroke studies,³⁵ and facilitate early definitive diagnosis and operative intervention in nontraumatic intracranial hemorrhage.³⁶ It is important to note that helicopter transfer of stroke patients for potential thrombolysis is cost-effective for a wide range of system variables.³⁷

Protocols for the use of air medical transfer from facilities unable to provide acute stroke care should be developed in advance. Air medical transfer should be considered for patients who cannot receive treatment locally and who could reach a treating facility within the available time window.^33,38

In addition, telemedicine may be used as a way to bring stroke expertise to patients in rural or small hospitals. Preliminary data suggest that such electronic methods may be increasingly useful.^39–43

D. Conclusions and Recommendations

Public educational programs likely will increase the proportion of patients with stroke who will utilize EMS as their first contact with the healthcare system. This trend should be encouraged. In response, EMS should have protocols in place to rapidly assess, treat, and transport patients. The objectives of the EMS phase of stroke care are as follows: (1) rapid identification of stroke as the cause of the patient’s findings, (2) elimination of comorbid conditions that could mimic stroke, (3) stabilization, (4) rapid transportation of the patient to the closest appropriate ED, and (5) notification of the receiving institution about impending arrival of a patient with suspected stroke. Such steps are especially critical for the use of time-dependent therapies. Community and physician educational programs on acute stroke treatment appear to enhance the use of recombinant tPA (rtPA), and these programs should be encouraged. Strategies such as telemedicine or air medical transport (helicopter) may provide access to specialized stroke care when it is not available locally. Such approaches may increase the number of patients who can be treated, especially in rural or otherwise underserved areas. To maximize therapeutic options, treatment guidelines and transfer protocols should be established in advance to ensure orderly patient transition from a prehospital to a hospital environment.

The recommendations that follow were not included in the previous guidelines.

A. Stroke Center Certification

The certification or designation of some hospitals as PSCs or CSCs is progressing rapidly. The American Stroke Association convened an expert panel to study this issue for PSCs, with the conclusion that a variety of certification processes might be developed and lead to improved care and outcomes.⁵⁷ Another panel is currently meeting to evaluate various options for CSC certification. One study showed that self-certification was likely to lead to a significant overestimation of a hospital’s compliance with published recommendations for a PSC.⁵⁸ Thus, these data and anecdotal experience suggest that outside independent evaluations of hospitals as stroke centers should lead to more accurate assessment of a facility’s true capabilities.

The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) began a formal process for the certification of PSCs in February 2004 (Table 6). As of February 2006, ≈200 hospitals in the United States had been certified as PSCs by the JCAHO. The JCAHO certification process includes a detailed evaluation of a hospital’s staffing, education, disease management programs, outcomes, and infrastructure (see www.JCAHO.org for details). Several states have developed or are exploring a state-based certification process for PSCs, primarily using the state health department or a related government agency as the certifier. At this time the American Stroke Association and JCAHO have taken preliminary steps that may lead to a formal certification process for CSCs.

The preferential routing of acute stroke patients to a PSC has been demonstrated to increase the proportion of patients cared for at stroke-capable centers and to increase the proportion of patients treated with thrombolytic therapy to >10%.⁴⁸ Direct routing of stroke patients whose symptoms started <3 hours ago to a PSC or a CSC has been implemented or is in the process of implementation in 7 states, covering >25% of the US population. The states of Florida, New Jersey, Maryland, Massachusetts, New Mexico, New York, and Texas have laws or policies mandating that acute stroke patients be taken to the nearest stroke center. In other states, the limited number of such centers makes preferential routing logistically infeasible. Stroke centers in rural areas often use helicopter transportation or telemedicine technologies to provide rapid transportation and expertise to expedite treatment at outlying hospitals.^33,53 However, this is clearly an area that will evolve as the number of stroke centers increases, their geographic distribution expands, and the concept is embraced by the medical community.

Stroke centers should not be viewed in isolation. Rather, they should be part of a larger support network sometimes referred to as a stroke system of care. Such a system would encompass issues such as prevention, education, acute care, rehabilitation, and quality improvement.⁵⁹ In addition, as the number of stroke centers increases, such facilities may form a network of hospitals that would be useful for testing new therapies for acute stroke.

B. Conclusions and Recommendations

Robust data demonstrate the efficacy of specialized stroke services in improving outcomes of patients with stroke. Thus, there is a strong impetus to develop such specialized stroke services across the United States. Both primary (PSC) and comprehensive (CSC) centers are needed. At present, the process of identification of PSCs is ahead of that used to develop CSCs. The details of the organization of such services may vary among institutions or in different parts of the country to reflect demographic or geographic variables. Statewide or regional programs are being developed. A method to designate stroke centers, such as the JCAHO program, is being used to ensure that centers have the expertise and resources to provide modern stroke care. Plans for EMS to bypass institutions that do not have the capability to provide modern stroke care need to be developed.

The following recommendations were not included in the prior stroke guidelines.

A. Immediate Evaluation

The initial evaluation of a potential stroke patient is similar to that of other critically ill patients: stabilization of the ABCs. This is quickly followed by a secondary assessment of neurological deficits and possible comorbidities. The overall goal is not only to identify patients with possible stroke but also to exclude stroke mimics (conditions with stroke-like symptoms), identify other conditions requiring immediate intervention, and determine potential causes of the stroke for early secondary prevention (Table 7).

B. Conclusions and Recommendations

The evaluation and initial treatment of patients with stroke should be performed as a priority in the hospital ED. The development of an organized protocol and stroke team should speed the clinical assessment, the performance of diagnostic studies, and decisions for early management. The clinical assessment (history, general examination, and neurological examination) remains the cornerstone of the evaluation. This evaluation should be performed by the physicians in the ED. The goals are to determine whether the patient has had a stroke and to establish potential contraindications for emergency treatment with agents such as rtPA. A stroke rating scale, such as the NIHSS, provides important information about the severity of stroke. It provides prognostic information, and the score may influence decisions about acute treatment. Some of the recommendations included in the present statement are influenced by the NIHSS. This scale can be performed with a reasonable degree of accuracy by practitioners in a broad range of specialties. Education in the nuances of NIHSS can improve the accuracy of this scale.

Because time is critical, a limited number of diagnostic tests are recommended. These tests should be available on a 24-hours-per-day, 7-days-per-week basis. These tests are used to screen for ischemic stroke, to exclude important alternative diagnoses (especially intracerebral hemorrhage), to assess for serious comorbid diseases, and to search for acute medical or neurological complications of the stroke (Table 9). Examination of the cerebrospinal fluid has a limited role in the evaluation of patients with suspected stroke. Additional diagnostic studies, including cardiac and vascular imaging, often are time consuming and may delay emergency treatment. Thus, most of these tests are not done until after the acute treatment or after the patient is admitted to the hospital.

The recommendations that follow are similar to those included in previous statements except recommendation 1 under Class III.

A. Brain Imaging

As therapeutic options evolve, brain imaging strategies are playing an increasingly important role in the initial evaluation of patients with acute stroke (Table 9). Brain imaging findings, including the size, location, and vascular distribution of the infarction, as well as the presence of bleeding, affect both short-term and long-term treatment decisions. In addition, information about the possible degree of reversibility of ischemic injury, intracranial vessel status, and cerebral hemodynamic status may be obtained by modern imaging studies.⁸⁵ Neuroimaging tests might improve selection of patients who could be treated with reperfusion therapies by identifying those with regions of salvageable brain tissue, a low risk for hemorrhagic transformation, or occlusions of large arteries that might or might not be amenable to therapy. CT and magnetic resonance imaging (MRI) are being used as initial imaging options. The most commonly obtained brain imaging test is noncontrast CT, but individual centers able to obtain MRI with efficiency equal to that of CT are using an MRI strategy in patients without MR contraindications.^86–90 Additional research is required.^91,92 As a result, it is generally agreed that the performance of these tests should not delay treatment with intravenous rtPA.^86,91–93

B. Other Vascular Imaging

In addition to the aforementioned CT and MR angiography, transcranial Doppler ultrasonography, carotid duplex sonography, and catheter angiography have been used to detect intracranial or extracranial vessel abnormalities. Transcranial Doppler ultrasonography and angiography have been used to monitor the effects of thrombolytic therapy over time and can help to determine prognosis.^177–179

In patients whose symptoms started <8 hours ago, these tests may be helpful in selecting candidates for intervention. A variety of ancillary tests are available to help clinicians reach accurate pathophysiological and etiologic stroke diagnoses and provide information that can be critical for effective prevention of recurrent stroke.^180,181 Vascular imaging is a key component of the evaluation. The selection of tests needs to be tailored to the individual patient and clinical setting.

C. Conclusions and Recommendations

Brain imaging remains a required component of the emergency assessment of patients with suspected stroke. Both CT and MRI are options for imaging the brain, but for most cases and at most institutions, CT remains the most practical initial brain imaging test. A physician skilled in assessing CT or MRI studies should be available to examine the initial scan. In particular, the scan should be evaluated for evidence of early signs of infarction. Baseline CT findings, including the presence of ischemic changes involving more than one third of a hemisphere, have not been predictors of responses to treatment with rtPA when the agent is administered within the 3-hour treatment window. Information about multimodal CT and MRI of the brain suggests that these diagnostic studies may help in the diagnosis and treatment of patients with acute stroke. Imaging of the intracranial or extracranial vasculature in the emergency assessment of patients with suspected stroke is useful at institutions providing endovascular recanalization therapies. The usefulness of vascular imaging for predicting responses to treatment before intravenous administration of thrombolytic agents has not been demonstrated.

A. Airway, Ventilatory Support, and Supplemental Oxygen

Maintaining adequate tissue oxygenation is important in the setting of acute cerebral ischemia. The goals are to prevent hypoxia and potential worsening of the brain injury. The most common causes of hypoxia are partial airway obstruction, hypoventilation, aspiration pneumonia, and atelectasis. Patients with decreased consciousness or signs of brain stem dysfunction have the greatest risk of airway compromise because of impaired oropharyngeal mobility and loss of protective reflexes.^182–184 The prognosis of patients who require endotracheal intubation generally is poor; ≈50% of these patients are dead within 30 days after stroke.^185,186 Pneumonia is among the leading complications of stroke and is an important cause of death after the cerebrovascular event.¹⁸⁷ It is most likely to develop among patients who are seriously ill, and prevention of early aspiration and protection of the airway may be a way to lessen this complication.

Elective intubation also may help in the management of patients who have severely increased levels of intracranial pressure or have malignant brain edema after stroke.^185,188 No clinical trial has tested the utility of endotracheal intubation in the management of critically ill patients with stroke, and we anticipate that none will be done. It is generally agreed that an endotracheal tube should be placed if the airway is threatened.^182,188

After ischemic stroke, some patients develop Cheyne-Stokes pattern of respiration, with decreases in oxygen saturation that can be readily reversed with oxygen supplementation.¹⁸⁹ A small pilot study found that high-flow oxygen may be associated with a transient improvement in neurological impairments.¹⁹⁰ The results of a controlled study do not support the use of supplemental oxygen at 3 L/min for most patients with acute ischemic stroke.¹⁹¹ However, patients with acute stroke should be monitored with pulse oximetry with a target oxygen saturation level ≥92%.^25,192 Most patients with acute stroke do not need supplemental oxygen; however, if pulse oximetry or blood gas determination indicates hypoxia, oxygen should be administered.

Hyperbaric oxygen may be used to treat patients with ischemic neurological symptoms secondary to air embolism or caisson disease.¹⁹³ Studies that have tested the use of hyperbaric oxygen in stroke have been inconclusive or have shown that the intervention does not improve outcomes.^194–196 Data from a small trial suggest that hyperbaric oxygen therapy may be harmful.¹⁹⁶ A systematic review found no evidence that hyperbaric oxygen improved outcomes after stroke or brain injury.¹⁹⁷ At present, data do not support the routine use of hyperbaric oxygen in the treatment of patients with acute ischemic stroke.

B. Temperature

Increased body temperature (fever) in the setting of acute ischemic stroke is associated with poor neurological outcome (increased risk of morbidity and mortality), possibly secondary to increased metabolic demands, enhanced release of neurotransmitters, and increased free radical production.^198–205 The source of any fever should be ascertained. The fever may be secondary to a cause of stroke, such as infective endocarditis, or may represent a complication, such as pneumonia.

Because of the negative effects of fever, lowering an acutely elevated body temperature might improve the prognosis of patients with stroke.²⁰⁶ Measures include antipyretic medications and cooling devices. Small clinical trials have tested the utility of aspirin, ibuprofen, or acetaminophen in lowering body temperatures and in improving outcomes after stroke. Sulter et al²⁰⁷ found that either aspirin or acetaminophen was modestly successful in achieving normothermia but that patients with a temperature >38°C were relatively unresponsive to treatment. In a small, randomized trial, Kasner et al²⁰⁸ administered 3900 mg of acetaminophen daily to afebrile patients with stroke. They concluded that the medication might prevent hyperthermia or modestly promote hypothermia but that the effects were not likely to have a robust clinical impact. Dippel et al²⁰⁹ tested 2 different doses of acetaminophen in a small clinical trial. They concluded that a daily dosage of 6000 mg might have a potential beneficial effect in lowering body temperature. A small placebo-controlled trial found that acetaminophen might lower body temperature by a mean of 0.26°C within 4 hours of starting treatment.²¹⁰ In another clinical trial, Dippel et al²¹⁰ compared the effects of placebo, ibuprofen, or acetaminophen on body temperature in 75 patients with recent stroke. Although treating fever after stroke makes intuitive sense, no data demonstrate that the use of medications to lower body temperature among either febrile or afebrile patients improves neurological outcomes after stroke. Seeking and treating the source of fever are reasonable.

Hypothermia has been shown to be neuroprotective in experimental and focal hypoxic brain injury models. Hypothermia may delay depletion of energy reserves, lessen intracellular acidosis, slow influx of calcium into ischemic cells, suppress production of oxygen free radicals, and lessen the impact of excitatory amino acids.²¹¹ Deep hypothermia often is administered to protect the brain in major operative procedures. Mild to moderate hypothermia is associated with improved neurological outcomes among patients with cardiac arrest.^212–214 Conversely, a multicenter clinical trial found that mild hypothermia administered during surgery for treatment of a ruptured intracranial aneurysm did not improve outcomes after subarachnoid hemorrhage.²¹⁵ Several small clinical studies have evaluated the feasibility of inducing modest hypothermia for treatment of patients with acute ischemic stroke.^216–223 Two small studies evaluated the utility of hypothermia in treating patients with malignant cerebral infarctions; results were mixed.^224,225 Potential side effects of therapeutic hypothermia include hypotension, cardiac arrhythmias, and pneumonia.²²⁶ In a systematic review of available data, Correia et al²²⁷ could find no evidence that physical cooling would improve outcomes after stroke. Although strong experimental and clinical evidence indicates that induced hypothermia can protect the brain in the presence of hypoxia or ischemia, including after cardiac arrest, data about the utility of induced hypothermia for treatment of patients with stroke are not yet available. Hypothermia is discussed in more detail in the neuroprotection section of this statement.

C. Cardiac Monitoring and Treatment

Although patients with heart disease are at high risk for ischemic stroke, both myocardial ischemia and cardiac arrhythmias are potential complications of acute cerebrovascular diseases.^228,229 Patients with infarctions of the right hemisphere, particularly those involving the insula, may have an increased risk of cardiac complications, presumably secondary to disturbances in autonomic nervous system function.^78,230–234 ECG changes secondary to stroke include ST-segment depression, QT dispersion, inverted T waves, and prominent U waves.^235–237 Elevations in blood levels of enzymes attributable to injury to myocardial muscle also may be found.⁷⁹ The most common arrhythmia detected in the setting of stroke is atrial fibrillation, which either may be related to the cause of stroke or may be a complication. Other potentially life-threatening cardiac arrhythmias are relatively uncommon, but sudden death may occur.^77,238 No clinical trials have tested the utility of cardiac monitoring for most patients with ischemic stroke or the use of cardiac protective agents or medications to prevent serious cardiac arrhythmias. Still, general consensus exists that patients with acute ischemic stroke should have cardiac monitoring for at least the first 24 hours and that any serious cardiac arrhythmia should be treated. The utility of prophylactic administration of medications to prevent cardiac arrhythmias among patients with stroke is not known.

D. Arterial Hypertension

An elevated blood pressure is often detected in the first hours after stroke. Elevations in blood pressure >160 mm Hg are detected in >60% of patients with acute stroke.²³⁹ Both elevated and low blood pressures are associated with poor outcome after stroke.²⁴⁰ For every 10-mm Hg increase >180 mm Hg, the risk of neurological deterioration increased by 40% and the risk of poor outcome increased by 23%. The elevation in blood pressure may be secondary to the stress of the cerebrovascular event, a full bladder, nausea, pain, preexisting hypertension, a physiological response to hypoxia, or a response to increased intracranial pressure.^241,242 In a study that correlated acute blood pressure values with other findings in the setting of acute stroke, Vemmos et al²⁴³ found that among patients with most subtypes of ischemic stroke, elevated blood pressure was correlated with a past history of hypertension or severity of neurological impairments. The same investigators found a U-shaped relationship between death and admission blood pressure; both elevated and low admission levels were associated with high rates of early and late death.²⁴³ They also correlated death due to brain injury and brain edema with high initial blood pressure levels. Castillo et al²⁴⁰ have reported similar findings. Using the data from the Glycine Antagonist in Neuroprotection (GAIN) study, Aslanyan et al²⁴⁴ found that an elevated baseline mean arterial blood pressure was not independently associated with an unfavorable outcome after stroke. However, elevations in mean blood pressure during the first days after stroke had an unfavorable effect on outcomes. The same investigators showed that an elevated pulse pressure (the difference between systolic and diastolic blood pressure values) was independently associated with poor outcomes 3 months after stroke.²⁴⁵

Theoretical reasons for lowering blood pressure include reducing the formation of brain edema, lessening the risk of hemorrhagic transformation of the infarction, preventing further vascular damage, and forestalling early recurrent stroke. In addition, urgent antihypertensive therapy may be needed to treat patients with stroke who also have hypertensive encephalopathy, aortic dissection, acute renal failure, acute pulmonary edema, or acute myocardial infarction.^242,246 Conversely, aggressive treatment of blood pressure may lead to neurological worsening by reducing perfusion pressure to ischemic areas of the brain.^242,247,248

In a majority of patients, a decline in blood pressure occurs within the first hours after stroke even without any specific medical treatment.²⁴¹ The blood pressure often falls spontaneously when the patient is moved to a quiet room, the patient is allowed to rest, the bladder is emptied, or the pain is controlled. In addition, treatment of increased intracranial pressure may result in a decline in arterial blood pressure.

There are several questions about the management of arterial hypertension in the setting of acute stroke.^249–251 Should patients previously taking antihypertensive medications continue taking them during the first hours after stroke? Are some of these medications contraindicated or indicated? Should new antihypertensive agents be started? What level of blood pressure would mandate initiation of new antihypertensive treatment? Which medication should be administered in this situation? Unfortunately, definite answers to these questions are not available. Since the publication of the last guidelines, several clinical studies have provided additional information.

A randomized trial testing nimodipine found that unfavorable outcomes among patients treated with the medication were associated with lowering of the blood pressure.^252,253 Reanalyzing some of the data from the studies of nimodipine, Fogelholm et al²⁵⁴ noted that favorable outcomes were associated with higher levels of blood pressure among patients with mild to moderate strokes receiving nimodipine. The converse was true among patients with severe strokes. In a study that involved 115 patients admitted within 24 hours of stroke, Oliveira-Filho et al²⁵⁵ noted that systolic blood pressure dropped by ≈28% during the first day whether or not medications were prescribed. They noted an adverse effect on outcomes with lowering of the blood pressure, with an association found with degree in decline. Each 10% decline was associated with an increased odds ratio of 1.89 in unfavorable outcomes. The impact was similar to the effects of age or NIHSS scores. Castillo et al²⁴⁰ noted that drops in either systolic or diastolic blood pressure of >20 mm Hg were associated with early neurological worsening, higher rates of poor outcomes or death, and larger volumes of infarctions. They noted that the early administration of antihypertensive agents to patients with systolic blood pressures >180 mm Hg was associated with a marked increase in likelihood of early deterioration, poor neurological outcome, or death.

Several small inconclusive studies have tested calcium channel–blocking agents, angiotensin-converting enzyme inhibitors, diuretics, β-blockers, and nitrates, with generally inconclusive or conflicting results.^256,257 A multicenter, placebo-controlled trial tested the utility of candesartan when started 1 day after stroke.²⁵⁸ The dosage of medication was increased on day 2 if the patient’s systolic blood pressure was >160 mm Hg systolic or >100 mm Hg diastolic. Rescue therapy with intravenous antihypertensive agents was permitted for patients with severely elevated blood pressures. At day 7, other antihypertensive agents could be administered to treat persisting elevated blood pressures. The trial was halted prematurely because of a higher rate of deaths and recurrent vascular events in the placebo-treated group. However, the differences in outcomes were not seen in the first few months after stroke, and the divergence between treatment groups was seen only after 1 year. In a small study, patients were given either captopril or amlodipine for treatment of hypertension beginning 1 day after stroke; moderate reductions in blood pressure were associated with improved short-term outcomes.²⁵⁹ In another small, randomized study, Eames et al²⁶⁰ found no major reduction in blood pressure among patients treated with bendrofluazide, and they concluded that this agent was not effective in treating hypertension after stroke. Large, well-designed trials are needed to clarify the management of arterial hypertension after acute stroke. A trial testing the utility of antihypertensive therapy in the setting of stroke (Controlling Hypertension and Hypotension Immediately Post-Stroke [CHHIPS]) is ongoing.²⁶¹

Because of the lack of unambiguous data, the appropriate treatment of arterial hypertension in the setting of acute ischemic stroke remains controversial. Although severe hypertension may be considered an indication for treatment, no data define the levels of arterial hypertension that mandate emergency management.²⁴⁷ However, the aforementioned data suggest that the systolic blood pressure level that would prompt treatment would be >180 mm Hg.²⁴⁰ A systolic blood pressure >185 mm Hg or a diastolic blood pressure >110 mm Hg is a contraindication to intravenous administration of rtPA.^66,262 Still, it is not clear whether those values should be the threshold for starting emergency treatment outside the setting of administration of rtPA. Although no definitive data from controlled trials are available, in the absence of other organ dysfunction necessitating rapid reduction in blood pressure or in the setting of thrombolytic therapy, there is little scientific evidence and no clinically established benefit for rapid lowering of blood pressure among persons with acute ischemic stroke.²⁴⁷ Some data indicate that rapid and steep reductions in blood pressure might be harmful. Pending more data, the consensus of the panel is that emergency administration of antihypertensive agents should be withheld unless the diastolic blood pressure is >120 mm Hg or unless the systolic blood pressure is >220 mm Hg. The panel recognizes that no data show that these values are especially dangerous and emergency treatment is needed. However, the panel remains concerned by the evidence that aggressive lowering of blood pressure among patients may cause neurological worsening, and the goal is to avoid overtreating patients with stroke until definitive data are available.

When treatment is indicated, lowering the blood pressure should be done cautiously. Some strokes may be secondary to hemodynamic factors, and a declining blood pressure may lead to neurological worsening. A reasonable goal would be to lower blood pressure by 15% to 25% within the first day.²⁶³ Because no data support the administration of any specific antihypertensive agent in the setting of acute ischemic stroke, the treating physician should select medications for lowering blood pressure on a case-by-case basis. The recommendations in Table 10 are based on consensus and reflect the goal of rapidly reducing blood pressure, but, at the same time, the potential for a rapid reversal if the drop in blood pressure leads to neurological worsening. The selection of an agent may be influenced by other medical conditions; for example, the presence of asthma would contraindicate the administration of a β-blocker. Because of a prolonged effect and the potential for a precipitous decline in blood pressure associated with the sublingual administration of nifedipine, this agent with this route of administration is not recommended.²⁶⁴

Among patients who are candidates for treatment with intravenous rtPA, attention to management of blood pressure is critical before, during, and after the administration of the medication.²⁶³ Excessively high blood pressure is associated with an increased risk of symptomatic hemorrhagic transformation.^{66,262,265,266} Failure to meet the blood pressure parameters of previous guidelines may be one of the explanations for an increased risk of hemorrhagic complications after administration of rtPA.^267–269 Presumably, similar risks of bleeding will be associated with elevations of blood pressure among patients receiving other acute pharmacological or mechanical interventions to improve the perfusion to the brain. The suggestion to withhold such therapies among patients with markedly elevated blood pressure is based on potential safety risks. Conversely, excessively high blood pressures could be lowered successfully with medications to permit treatment with intravenous rtPA.

Arterial hypertension is a recognized risk factor for stroke and recurrent stroke. Many patients were taking medications before their stroke or are found to have sustained hypertension after their stroke. These patients will need long-term antihypertensive treatment; the primary question is the timing of the institution of such therapy. Limited data are available to guide these decisions. On the basis of the trial of candesartan, it appears that medications can be administered with a reasonable degree of safety when started ≈1 day after stroke.²⁵⁸ The timing of the reinstitution of treatment and the selection of medications will depend on the patient’s neurological status, the underlying stroke mechanism, the patient’s ability to swallow medications, and the presence of concomitant diseases. Presumably, most patients with mild to moderate strokes who are not at high risk for increased intracranial pressure may have their prestroke antihypertensive medications restarted 24 hours after their vascular event. The panel strongly endorses clinical research that will provide information about the safety and efficacy of restarting antihypertensive therapy among patients with stroke.

E. Arterial Hypotension

Persistent arterial hypotension is rare among patients with acute ischemic stroke, but it is associated with an increased likelihood of an unfavorable outcome.²⁷⁰ Castillo et al²⁴⁰ noted that the rates of neurological worsening, poor neurological outcomes, or death increased when the baseline systolic blood pressure was <100 mm Hg or the diastolic blood pressure was <70 mm Hg. The cause of hypotension should be sought; among the potential causes are aortic dissection, volume depletion, blood loss, and decreased cardiac output secondary to myocardial ischemia or cardiac arrhythmias. Patients with stroke may have depleted blood volume. Correction of hypovolemia and optimization of cardiac output are important priorities during the first hours after stroke. Treatment includes volume replacement with normal saline and correction of cardiac arrhythmias, such as slowing a ventricular response to rapid atrial fibrillation. If these measures are ineffective, vasopressor agents such as dopamine may be used. Trials have tested the utility of volume expansion and drug-induced hypertension for treatment of acute ischemic stroke. These measures are described later in the present guideline.

F. Hypoglycemia

Because hypoglycemia may produce neurological signs that mimic ischemic stroke and because hypoglycemia itself may lead to brain injury, prompt measurement of the serum glucose concentration and rapid correction of a low serum glucose level are important.

G. Hyperglycemia

Hyperglycemia will be detected on admission in approximately one third of patients with stroke.^271–273 Most patients have moderate elevations of glucose levels.²⁷⁴ Clinical studies demonstrate that the presence of hyperglycemia is associated with poor outcomes after ischemic stroke, including among patients treated with thrombolytic agents.^275–279 A history of diabetes mellitus also is associated with a poorer outcome after stroke.^280,281

The detrimental effects of hyperglycemia are not clearly understood but include increasing tissue acidosis secondary to anaerobic glycolysis, lactic acidosis, and free radical production.^281,282 Hyperglycemia also may affect the blood–brain barrier and the development of brain edema²⁸¹ and may be associated with an increased risk of hemorrhagic transformation of the infarction.²⁸³ Unfortunately, the contribution of hyperglycemia to poor outcomes may be affected by other factors.²⁸⁴ Elevations of blood glucose concentration may be secondary to the stress of the acute cerebrovascular event.²⁸⁵ In particular, hyperglycemia after stroke in nondiabetic patients may be a stress response.²⁸⁵ Candelise et al²⁸⁶ found that hyperglycemia is a marker of a more severe stroke. Thus, the poor outcomes among patients with hyperglycemia may in part reflect the seriousness of the vascular event itself. Recent clinical and imaging studies have highlighted the importance of hyperglycemia as a negative prognostic factor.^{271,278–280,282} Baird et al²⁸⁰ found that persistent hyperglycemia (blood glucose level >200 mg/dL) during the first 24 hours after stroke independently predicted expansion of the volume of ischemic stroke and poor neurological outcomes. These reports provide reasonable evidence that persistent elevations of blood glucose levels are associated with neurological worsening.^281,287 These data suggest that management of hyperglycemia is an important part of acute management of patients with ischemic stroke. The outstanding issues relate to the effectiveness of management of stroke-associated hyperglycemia in improving outcomes after stroke and the level of glucose concentration that should be sought during the first 24 hours. On the basis of the aforementioned data, the panel concluded that the level of hyperglycemia that previously mandated emergency treatment in the setting of stroke was too high. The exact level of blood glucose that should prompt interventions is not known. A reasonable approach would be to initiate treatment among patients with a blood glucose level >200 mg/dL. The management of hyperglycemia among patients with stroke likely will be influenced by the approach to treating elevated blood glucose levels among patients with other critical illnesses, including patients who have had cardiac arrest. The changes are dramatic. Several studies have looked at the utility of intensive insulin protocols in treating critically ill patients with a broad range of illnesses.^288–293 In general, the desired level of blood glucose has been in the range of 80 to 140 mg/dL. Frequent monitoring of blood glucose levels and adjustments of insulin are required. These studies have demonstrated a reduction in death and important complications, including infections and renal failure, with aggressive management of hyperglycemia. The frequency of hypoglycemic episodes appears to be low. Physicians treating patients with severe stroke should be aware of the new regimens for treating hyperglycemia. Gray et al²⁷⁴ found that plasma glucose levels spontaneously decline in many patients. A small clinical trial tested the safety of short-term administration of glucose, insulin, and potassium to patients with moderate hyperglycemia.²⁹⁴ The intervention could be given safely, but plasma glucose levels were not significantly lower than in the control group. A subsequent report about a larger cohort treated by the same investigators found that infusions of glucose, insulin, and potassium significantly reduced blood pressure, but no differences in outcomes were noted 7 days after stroke.²⁹⁵ Bruno et al²⁹⁶ treated 24 patients with markedly elevated serum glucose levels (mean 14.7 mmol/L) within 12 hours of onset of stroke. With insulin infusions that required frequent adjustments in response to serum levels, they were able to achieve desired glucose control within 5 hours. Symptomatic hypoglycemia occurred in 5 patients. It is unclear whether the intervention affected outcomes. A British trial (United Kingdom Glucose Insulin in Stroke Trial) is testing the utility of a strategy of achieving euglycemia after stroke.²⁷⁴ Despite the lack of data to guide decisions about management, consensus exists that hyperglycemia should be controlled after stroke.²⁹⁷ A reasonable goal would be to treat those patients’ elevated glucose concentrations (140 to 180 mg/dL). The approach would be similar to that prescribed for other acutely ill patients with concomitant hyperglycemia.

H. Conclusions and Recommendations

Most of the recommendations about general acute management are based on limited data. Some of the aspects of acute management may never be tested in clinical trials, whereas other aspects of treatment, such as the best strategy for treatment of hyperglycemia or arterial hypertension, likely will be clarified by ongoing or future clinical research. Pending such trials, many of the suggestions that follow are based on consensus and thus are Grade C recommendations.

A. Recombinant Tissue Plasminogen Activator

Intravenous thrombolytic therapy for acute stroke is now generally accepted.²⁹⁸ The US Food and Drug Administration (FDA) approved the use of intravenous rtPA in 1996, partly on the basis of the results of the NINDS rtPA Stroke Study, in which 624 patients with ischemic stroke were treated with placebo or rtPA (0.9 mg/kg IV, maximum 90 mg) within 3 hours of symptom onset, with approximately one half treated within 90 minutes.⁶⁶ The study was conducted in 2 parts. In part I, the primary end point was neurological improvement at 24 hours, as indicated by complete neurological recovery or an improvement of ≥4 points on the NIHSS. In part II, the pivotal efficacy trial, the primary end point was a global odds ratio for a favorable outcome, defined as complete or nearly complete neurological recovery 3 months after stroke. Favorable outcomes were achieved in 31% to 50% of patients treated with rtPA, as compared with 20% to 38% of patients given placebo. The benefit was similar 1 year after stroke.²⁹⁹ The major risk of treatment was symptomatic brain hemorrhage, which occurred in 6.4% of patients treated with rtPA and 0.6% of patients given placebo. However, the death rate in the 2 treatment groups was similar at 3 months (17% versus 20%) and 1 year (24% versus 28%).^66,299 Although the presence of edema or mass effect on baseline CT scan was associated with higher risk of symptomatic intracranial hemorrhage, follow-up study demonstrated that the presence of early ischemic changes on CT scan was not associated with adverse outcome.^100,266 Indeed, in the Australian trial of streptokinase, early CT evidence of edema was not associated with an increased risk of hemorrhagic conversion.³⁰¹ The likelihood of favorable outcome also was affected by the severity of deficits and the patient’s age. Patients with mild to moderate strokes (NIHSS score <20) and persons younger than 75 years of age had the greatest potential for a favorable response to treatment.³⁰² The chances of a complete or nearly complete recovery among patients with severe stroke (NIHSS score of ≥20) improved with treatment, but overall success in this group of critically ill patients was low.³⁰² In 2 large trials, the European Cooperative Acute Stroke Study (ECASS) and ECASS-II, intravenous rtPA was not more effective than placebo in improving neurological outcomes 3 months after stroke.^303,304 The dosage of rtPA used in ECASS was marginally higher than that used in the NINDS trials, and patients were treated up to 6 hours after stroke. Patients with CT evidence of low attenuation (edema and/or ischemia) involving more than one third of the territory of the MCA were less likely to have a good outcome after treatment with rtPA than were those who received placebo.^98,305 However, the numbers were small, and the difference did not reach statistical significance. A post hoc analysis concluded that the patients treated within 3 hours appeared to benefit from rtPA.³⁰⁶ In the ECASS-II trial, 800 patients were assigned randomly to treatment with either rtPA (0.9 mg/kg IV) or placebo. More than one third of the patients in each group made an excellent recovery, and no significant benefit was noted from treatment. A post hoc analysis of ECASS-II showed that the likelihood of either death or dependency was lower among the patients treated with rtPA.³⁰³ The trial included vigorous methodology to avoid recruitment of patients with CT changes consistent with multilobar infarctions.⁹⁸ As a result, the strokes among the patients admitted in ECASS-II were less severe than in the other studies, and the generally more favorable prognosis among patients may have reduced the likelihood of detecting a therapeutic effect. Still, the rate of symptomatic intracranial hemorrhage was increased with rtPA treatment (8.8% versus 3.4%). An American trial tested rtPA up to 5 hours after stroke.³⁰⁷ Results were similar in that approximately one third of the patients in both treatment groups made an excellent recovery. The rate of symptomatic hemorrhage was higher in the treatment group (7% versus 1.1%). Subsequent to the approval of rtPA for treatment of patients with acute ischemic stroke, several groups reported on the utility of the treatment in a community setting.^{269,308–313} Some groups reported rates of intracranial hemorrhage and favorable outcomes that are similar to those found in the NINDS trials, but others have not. It is now clear that the risk of hemorrhage is proportional to the degree to which the NINDS protocol is not followed.^269,314,315 Besides a risk of intracranial hemorrhage, other potential adverse experiences include systemic bleeding, myocardial rupture if the agent is given within a few days of acute myocardial infarction, and reactions such as anaphylaxis or angioedema, although these events are rare.²⁹⁸ Debate about time of initiation of rtPA treatment merits attention. The NINDS investigators reported a time-to-treatment interaction in a subgroup analysis of the NINDS rtPA Trial.⁶⁰ Treatment with rtPA initiated within 90 minutes of symptom onset was associated with an odds ratio of 2.11 (95% confidence interval, 1.33 to 3.55) for favorable outcome at 3 months as compared with placebo. In comparison, the odds ratio for good outcome at 3 months for treatment with rtPA initiated within 90 to 180 minutes was 1.69 (95% confidence interval, 1.09 to 2.62). The investigators concluded that the earlier that treatment is initiated, the better the result. A subsequent pooled analysis of all large, multicenter, placebo-controlled trials of rtPA for acute stroke confirmed a time effect, but the upper limit of the treatment window may be as late as 5 to 6 hours.³¹⁶ Investigation of the early time epoch in the NINDS trial revealed a potential confounder in the original data: 19% of the patients treated with rtPA between 91 and 180 minutes after stroke onset had an NIHSS score of ≤5 compared with 4% of the placebo patients. On the basis of this observation, it has been suggested that the relative preponderance of mild strokes with a likely good outcome in the rtPA treatment group may explain the entire benefit reported for patients treated between 91 and 180 minutes. Subsequent reanalysis showed that the imbalance in patients with minor stroke did not explain the difference between treatment and placebo.³¹⁷ The adjusted odds ratio for 3-month favorable outcome (odds ratios for treatment compared with placebo) for the subgroup of patients from the NINDS rtPA Stroke Trial with NIHSS score of ≥5 at baseline and time from stroke onset to treatment of 91 to 180 minutes was statistically significant in favor of treatment. Indeed, when all possible subgroups were examined separately, no effect of the severity imbalance could be shown to influence the overall result that rtPA therapy positively influenced outcome. In a separate analysis by an independent group, an identical finding was reached: Baseline imbalances in the numbers of patients with mild stroke do not explain the overall study result.³¹⁸

B. Other Thrombolytic Agents

Clinical trials of streptokinase were halted prematurely because of unacceptably high rates of hemorrhage, and this agent should not be used.^319–322 Other intravenously administered thrombolytic agents, including reteplase, urokinase, anistreplase, and staphylokinase, might have been considered for treatment of patients with acute ischemic stroke. None of these agents has been tested extensively. Tenecteplase appears promising as an effective thrombolytic with fewer bleeding complications than wild-type rtPA, but pivotal studies are under way.³²³ Desmoteplase has been tested in a pilot study; results appear promising.^189,324

C. Defibrogenating Enzymes

Ancrod, an enzyme derived from snake venom that degrades fibrinogen, was tested in a series of clinical studies. A preliminary trial found that ancrod treatment improved outcomes after stroke, with patients with blood fibrinogen levels <100 mg/dL having the best responses.^325,326 A subsequent study found a favorable benefit–risk profile for patients. Further studies of ancrod continue, given the potentially favorable combination of antithrombotic activity and mild thrombolytic effect.^327,328

D. Conclusions and Recommendations

Intravenous administration of rtPA is the only FDA-approved medical therapy for treatment of patients with acute ischemic stroke.³ Its use is associated with improved outcomes for a broad spectrum of patients who can be treated within 3 hours of stroke onset. Earlier treatment (ie, within 90 minutes) may be more likely to result in a favorable outcome. Later treatment, at 90 to 180 minutes, also is beneficial. Patients with major strokes (NIHSS score >22) have a very poor prognosis, but some positive treatment effect with rtPA has been documented.³²⁹ Because the risk of hemorrhage is considerable among patients with severe deficits, the decision to treat with rtPA should be made with caution. Treatment with rtPA is associated with symptomatic intracranial hemorrhage, which may be fatal. In the original NINDS trials, the risk of symptomatic bleeding was ≈6%.¹⁰⁰ Recent community-based studies and registries report lower rates of hemorrhage.^{269,330–333} Recommendations for the management of intracranial hemorrhage after treatment with rtPA are provided in the AHA Stroke Council’s updated guideline statement on management of intracerebral hemorrhage, which is being issued contemporaneously with this statement. The best methods for preventing bleeding complications are careful selection of patients and scrupulous ancillary care, especially close observation, and monitoring of the patient with early treatment of arterial hypertension. Factors that affect decisions about administration of rtPA are outlined in Table 11, and the treatment regimen for administration of rtPA is included in Table 12. Case series have suggested that thrombolysis may be used in patients with seizures at the time of presentation when evidence suggests that residual deficits are due to ischemia rather than the postictal state.^334,335 The use of anticoagulants and antiplatelet agents should be delayed for 24 hours after treatment.

Although written consent is not necessary before administration of rtPA for treatment of stroke, a full discussion of the potential risks and benefits of treatment with rtPA with the family and the patient if possible is recommended.

Although other thrombolytic agents, including defibrinogenating drugs, are being tested, none has been established as effective or as a replacement for rtPA.

A. Conclusions and Recommendations

Since the publication of the last guidelines, no new Class I evidence has been published. Intra-arterial administration of at least one specific thrombolytic agent appears to be of benefit in the treatment of carefully selected patients with acute ischemic stroke secondary to occlusion of the MCA. New evidence about the use of intra-arterial urokinase in patients with vertebral or basilar artery occlusion treated within 24 hours of symptom onset and patients with embolic stroke involving the anterior circulation within 4.5 hours of symptom onset suggests that intra-arterial therapy may be used. Patients who are evaluated within 6 hours of symptoms but who are ineligible to receive intravenous thrombolysis because of recent surgery or other procedures may be candidates for intra-arterial thrombolysis.^345,346

New criteria have been established to determine the qualifications of physicians who can perform intra-arterial thrombolysis on the basis of recent statements from professional organizations and clinical trials.

A. Heparin

The International Stroke Trial tested 2 doses (5000 U/d or 25 000 U/d) of subcutaneously administered heparin when the medication was started within 48 hours of stroke.³⁶¹ Although the trial included randomization in its design, investigators and patients knew the nature of the treatment. Dual randomization meant that approximately one half of the patients receiving heparin also were receiving aspirin. Neither monitoring of the level of anticoagulation nor adjustment of dosages to biological responses was done. Thus, some patients may have received excessive doses of heparin, with an increased risk of bleeding complications, and others may have had inadequate dosages, with a resultant loss of effectiveness. In addition, patients enrolled in this very large trial did not need to have a brain imaging study before treatment. Although heparin was effective in lowering the risk of early recurrent stroke, an increased rate of bleeding complications negated this benefit. A subgroup analysis looking at the effects of heparin among patients with atrial fibrillation did not demonstrate a benefit from the agent.³⁶³

A Swedish study testing the utility of heparin for treatment of patients with progressing stroke did not demonstrate a benefit from the anticoagulant.³⁶⁴ Recently, 2 small European trials have tested the utility of heparin in treatment of patients with recent stroke.^365,366 Investigators tested continuously intravenously administered heparin starting with a bolus dose with adjustments in dosage in response to activated partial thromboplastin time in a small clinical trial that enrolled patients within 12 hours of onset of stroke. The multicenter trial treated 32 patients with heparin and 35 with aspirin (control). No significant differences in outcomes, recurrent ischemic stroke, hemorrhagic worsening, or death were noted between the 2 treatment groups. A single-center study involved the randomization of patients with acute nonlacunar hemispheric infarctions to treatment with either adjusted intravenous infusions of heparin without an initial bolus dose or saline.³⁶⁵ The trial enrolled 418 patients (208 on heparin) within 3 hours of onset of stroke. Thirteen heparin-treated patients had symptomatic hemorrhagic complications (6.2%) (7 were fatal), and symptomatic hemorrhagic events were diagnosed in 3 control patients (1.4%). Favorable outcomes at 90 days were noted in 81 of 208 patients treated with heparin (38.9%) and 60 of 210 patients (28.6%) in the control group. A meta-analysis of the studies of heparin found no benefit from administration of the medication.³⁶⁷ However, this analysis was performed before the 2 recent reports about heparin were published. Nevertheless, the results of the relatively small study by Camerlingo et al³⁶⁵ likely would be dwarfed by the data from the International Stroke Trial.

B. Low-Molecular-Weight Heparins and Danaparoid

Several trials have tested low-molecular-weight (LMW) heparins or danaparoid for treatment of patients with acute ischemic strokes. Results generally have been negative. A trial in Hong Kong tested 2 doses of subcutaneously administered nadroparin given over 10 days after stroke.³⁶⁸ Although no benefit from treatment was found at the end of the treatment period or at 3 months, those who received the larger dose of nadroparin had a significantly lower death rate at 6 months than did the control group. Another trial of nadroparin failed to find any improvement in the rate of favorable outcomes with treatment, but the rate of serious bleeding was increased with the larger of 2 doses of LMW heparin.³⁶⁹ Berge et al³⁵⁹ compared the utility of dalteparin or aspirin for prevention of early recurrent stroke or improvement in neurological outcome among patients with presumed cardioembolic stroke. Although no significant differences were noted in outcomes or the rates of recurrent strokes, the patients taking aspirin had fewer second events. The rate of bleeding complications also was higher among patients who were treated with dalteparin than among those given aspirin. A German trial compared 4 different doses of certoparin; no differences in rates of favorable outcomes were noted among the groups, but the rate of serious bleeding complications was highest among the group that received the largest dose of the LMW heparin.³⁷⁰ An aspirin-controlled trial tested 2 different doses of subcutaneously administered tinazaparin in patients with recent stroke, with no differences in favorable outcomes, rates of recurrent stroke, death, or bleeding complications.³⁷¹

A randomized, double-blind, placebo-controlled trial tested the utility of a continuous intravenous infusion of the LMW heparinoid (danaparoid) in improving outcomes after acute ischemic stroke.³⁶² The trial halted recruitment of patients with moderate to severe stroke (NIHSS scores of ≥15) because of an increased risk of symptomatic intracranial hemorrhages. The medication did not lessen the risk of neurological worsening or early recurrent stroke, including among patients with cardioembolic events. No improvement in the chance of having a favorable or very favorable outcome was found at 3 months. The trial included prespecified subgroup analyses among patients with different subtypes of ischemic stroke. The only subgroup that showed benefit from treatment included patients with stroke secondary to large-artery atherosclerosis.³⁷² This finding may be supported by the results of the study by Lovett et al,³⁷³ which found that the risk of early recurrent stroke was highest among patients with severe large-artery atherosclerotic disease. A study examining the usefulness of a LMW heparin in treating patients with stroke secondary to intracranial stenotic disease has been performed in Hong Kong and Singapore, but the results have not yet been published.

Some studies have compared the utility of heparin or LMW heparins in treatment of patients with recent stroke. Woessner et al³⁷⁴ compared the usefulness of subcutaneously administered enoxaparin or adjusted-dose heparin in a multicenter trial that randomized patients with either high-grade arterial stenoses or a cardioembolic source for stroke. No significant differences were noted between the 2 regimens. Another trial investigated the efficacy of subcutaneously administered enoxaparin in comparison to heparin for prevention of thromboembolic events among patients with lower-limb paralysis after stroke.³⁷⁵ The 2 medications had equal efficacy.

C. Anticoagulants as an Adjunctive Therapy

The administration of anticoagulants or antiplatelet agents is currently contraindicated during the first 24 hours after treatment with intravenous rtPA. This restriction is based on the regimen used in the NINDS trials.⁶⁶ Arterial reocclusion may follow successful recanalization with thrombolysis.³⁷⁶ Thus, there is interest in the use of an anticoagulant that may maintain arterial patency after thrombolytic therapy. The trials of intra-arterial administration of prourokinase used heparin as part of the treatment regimen, and the control group received only heparin.^336,377,378 In the first study, both the success of recanalization and the risk of hemorrhage were increased among the patients who received the larger of the 2 doses of adjunctive heparin. Two small studies have tested the use of intravenously administered heparin after treatment with rtPA.^379,380 No increase in bleeding complications has been reported. Heparin also has been given in combination with abciximab with a reasonable degree of safety.³⁸¹ The experience with adjunctive anticoagulation is limited. Neither safety nor effectiveness has been established, and additional research is needed.

D. Conclusions and Recommendations

The results of the recent trials show that early administration of either heparin or a LMW heparin/danaparoid is associated with an increased risk of bleeding complications. These medications increase the risk of symptomatic hemorrhagic transformation of ischemic strokes, especially among persons with severe events. These medications are also associated with a risk of serious bleeding in other parts of the body. Although the likelihood of bleeding appears to be lower than that associated with the administration of thrombolytic agents, it is sufficiently high to require convincing evidence of efficacy to justify urgent anticoagulation. The risk of bleeding appears not to be greatly affected by the use of a bolus dose to start treatment or by the route of administration (subcutaneous or intravenous). Monitoring of the level of anticoagulation and adjustment of the dosages in response to levels probably increase the safety of treatment.

Present data indicate that early administration of heparin or the LMW heparins/danaparoid does not lower the risk of early recurrent stroke, including among patients with cardioembolic stroke. Early administration of anticoagulants does not lessen the risk of early neurological worsening. Data are not sufficient to indicate whether anticoagulants might have efficacy among some potentially high-risk groups, such as persons with intracardiac or intra-arterial thrombi. The efficacy of urgent anticoagulation is not established for treatment of patients with vertebrobasilar disease or an arterial dissection.

Most trials have not demonstrated the efficacy of anticoagulation in improving outcomes after acute ischemic stroke. One relatively small trial found that intravenous heparin, when administered within 3 hours of onset of stroke to patients with nonlacunar stroke, may improve outcomes. In light of the generally negative data, the results of this trial may need to be replicated. Because the time window for potentially effective treatment with heparin is the same as for intravenously administered rtPA, a study may be needed to test the relative efficacy of heparin or thrombolysis.

The role of anticoagulants as an adjunctive therapy in addition to mechanical or pharmacological thrombolysis has not been defined.

The following recommendations have not changed from previous guidelines.

A. Single Oral Antiplatelet Agent

Aspirin is the only oral antiplatelet agent that has been evaluated for the treatment of acute ischemic stroke. Two large trials^360,361 each showed a nonsignificant trend in reduction in death or disability when treatment with aspirin was initiated within 48 hours of stroke. A small increase in bleeding complications was also noted. When the data from the 2 trials were combined, a modest but statistically significant benefit from aspirin was noted. The primary effect seemed to be in prevention of recurrent events. It is not clear whether aspirin limited the neurological consequences of the acute ischemic stroke itself.

The use of ticlopidine, clopidogrel, or dipyridamole in the setting of acute ischemic stroke has not been evaluated.³⁸² Initiation of treatment with clopidogrel in a daily dose of 75 mg does not cause maximal platelet inhibition for ≈5 days.³⁸³ This delay poses the issue of an early therapeutic effect for treatment of patients with acute stroke. A bolus dose of clopidogrel 300 mg inhibits platelet aggregation rapidly.³⁸⁴ A 300-mg loading dose of clopidogrel followed by daily doses of 75 mg/d has been recommended for treatment of patients with acute coronary syndrome (ACS) who have aspirin allergies.³⁸⁵ No data are available about the utility of this strategy in treating patients with acute ischemic stroke.^386,387

B. Combination of Oral Antiplatelet Agents

Although the combination of clopidogrel and aspirin is prescribed for patients with ACS, this combination has not been studied in the setting of acute ischemic stroke. No data are available about the use of other combinations of antiplatelet agents in the management of acute ischemic stroke.

C. Intravenous Antiplatelet Agents

The platelet glycoprotein IIb/IIIa inhibitors have been considered in the treatment of acute ischemic stroke because they may increase the rate of spontaneous recanalization and improve microvascular patency.^388,389 A small case series³⁹⁰ demonstrated that intravenous abciximab administered between 3 and 24 hours after symptom onset in patients with supratentorial ischemic stroke may attenuate ischemic lesion growth as demonstrated by serial DWI. A double-blind, placebo-controlled, dose-escalation trial randomly allocated 74 patients to receive either an escalating dose of abciximab (54 patients) or placebo (20 patients) in a 3:1 ratio within 24 hours after ischemic stroke onset.^390,391 No symptomatic intracerebral hemorrhages occurred in any group, which suggests that intravenous abciximab is relatively safe when administered within 24 hours of symptom onset in selected patients with ischemic stroke. A second randomized, double-blind, placebo-controlled phase II trial randomized 400 patients within 6 hours of ischemic stroke onset to intravenous abciximab or placebo.³⁹² The rates of symptomatic hemorrhage during the first 5 days after stroke were not significantly different between the abciximab and placebo groups (3.6% versus 1%). Treatment with abciximab showed a nonsignificant shift in favorable outcomes defined by modified Rankin Scale scores at 3 months, after adjustment for baseline severity of stroke, age, and interval from stroke.^391,392 A phase III, multinational, multicenter, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of abciximab in patients with acute ischemic stroke has been halted because of an increased rate of bleeding. Details are not yet available.

D. Conclusions and Recommendations

No new data are available about the utility of oral antiplatelet agents (used singly or in combination) for treatment of patients with acute ischemic stroke. Currently available data demonstrate a small but statistically significant decline in risk of mortality and morbidity when aspirin is started within 48 hours after onset of stroke. It appears that the primary effects of the aspirin are due to reduction of early recurrent stroke rather than limitation of the neurological consequences of the stroke. No data are available on the utility of other antiplatelet agents, including clopidogrel, given as monotherapy or in combination with aspirin for treatment of patients with acute ischemic stroke. The relative indications for the long-term administration of antiplatelet agents to prevent recurrent stroke are beyond the scope of this statement. However, the panel recommends the administration of such agents as part of management after acute stroke.

Ongoing research is testing the usefulness of intravenously administered antiplatelet agents (glycoprotein IIb/IIIa receptor blockers) when given alone or in combination with other interventions. Preliminary evidence suggests that these agents, when used alone, have an acceptable safety profile, but considerably more research is needed to determine whether these agents have a role in the management of acute stroke in conjunction with other therapies.

A. Hemodilution in Acute Ischemic Stroke

It is known that patients experiencing acute ischemic stroke may have a variety of abnormalities that increase whole-blood viscosity, including leukocyte activation, red cell aggregation, and reduced red cell deformability.^393–395 In addition, elevated fibrinogen levels, which add to plasma viscosity, have been documented. On the basis of these findings, hemodilution, with or without venesection, has been studied. The goal is to improve cerebral blood flow to hyperperfuse potentially viable brain tissue supplied by leptomeningeal collaterals in an attempt to perfuse the ischemic penumbra.^396–400

Volume expansion and hemodilution have been demonstrated to improve blood flow but may reduce oxygen-carrying capacity at hematocrits <30%.^401–408 As the hematocrit is reduced, oxygen delivery increases as much as 28% to 30%; however, at levels lower than this, oxygen delivery begins to decline.⁴⁰⁹

In patients with cerebral infarction, cerebral autoregulatory mechanisms are impaired, and hemodilution has been noted to increase cerebral blood flow in the infarcted as well as the contralateral hemisphere. Oxygen-carrying molecules such as perfluorocarbons or diaspirin cross-linked hemoglobin have been shown to reduce brain infarct size in animal models but have not yet been assessed and cannot be recommended in patients.^{383,410–417}

Investigations of intravascular volume and hemodilution in patients began in the 1960s. Initial reports, from studies that were not controlled and not randomized, were encouraging and suggested clinical benefits of intravascular volume expansion. In a review of recent trials for hemodilution in stroke, a combination of plasma volume expansion with or without venesection was used.^{387,416–422} Several trials used plasma volume expansion alone, either dextran 40 or hydroxyethyl starch and albumin in one trial.^{405,423–425} In all trials, and in the Multicenter Austrian Hemodilution Stroke Trial³⁸⁷ study in particular, hemodilution did not significantly reduce deaths within the first 4 weeks but did influence deaths within 3 to 6 months. Hemodilution also had no significant influence on death, dependency, or institutionalization/long-term care. In several trials, hemodilution was associated with a tendency toward reduction in deep venous thrombosis and pulmonary embolism at 3 to 6 months. Despite volume expansion and hemodilution, the risk of significant cardiac events did not increase.

B. Vasodilators in Acute Ischemic Stroke

Methylxanthine derivatives are known vasodilators that also have other activities such as inhibition of platelet aggregation, reduction of free radical release, and inhibition of thromboxane A₂ synthesis.^{404,427–429} On the basis of these characteristics, methylxanthine derivatives, specifically pentoxifylline, propentofylline, and pentifylline, have been evaluated in the setting of acute ischemic stroke.^430,431 In one trial, pentoxifylline and propentofylline were administered via continuous intravenous infusion over a 3-day period in patients experiencing an acute ischemic event.⁴³² Other studies continued infusions for 5 days, as in the trial by Chan and Kay in 1993, or 7 days, as in the trial of Huber et al in 1993.^433,434

Early case fatality, defined as within 4 weeks, was evaluated in several trials of pentoxifylline.^432–435 The trial conducted by Chan and Kay found a large reduction in the odds of early death; however, this was not borne out in other studies. Two trials demonstrated a nonsignificant reduction in early death or deterioration.^433,435 One trial compared the combination of pentoxifylline and aspirin with aspirin alone and found a significant decrease in short-term deaths.⁴³³ However, this trial studied early death and deterioration, and no significant reduction in these combined events was observed. The trial by Huber et al in 1993 included 30 patients after propentofylline treatment and found no difference in late case fatality.⁴³⁴ The trial by Chan and Kay administered aspirin to both patient groups with the theoretical advantage that aspirin may potentiate the antiplatelet effects of pentoxifylline, which may explain the apparent clinical effectiveness. The trial by Hsu et al demonstrated that patients with profound neurological deficit derived the greatest benefit from pentoxifylline.⁴³²

C. Induced Hypertension for the Management of Acute Ischemic Stroke

In the setting of acute stroke, patients may have an ischemic penumbra of brain tissue, which may have impaired perfusion but may not be irreversibly damaged. In this situation, a local drop in cerebral blood flow occurs, and cerebral arterioles dilate in an attempt to compensate and maintain flow to the potentially salvageable ischemic tissue.⁴³⁶ The magnitude of the low perfusion and duration of the ischemia are important variables.^437,438 It is intuitively attractive that reperfusion of this area by dilatation of leptomeningeal collaterals may be advantageous.

The optimal management of blood pressure in patients experiencing acute ischemic neurological events remains controversial.^247,439,440 Markedly elevated blood pressure after an acute ischemic event may increase the risk of conversion from an ischemic to a hemorrhagic lesion, with life-threatening implications.⁴⁴¹ However, inducing hypertension to increase cerebral blood flow has been attractive on the basis of experimental data.⁴³⁷ Preliminary studies suggest that there may be a role for induced hypertension.^{247,442–446} Other studies by Olsen demonstrated that the ischemic penumbra has impaired autoregulation and that induction of elevated blood pressure partially restores perfusion to the penumbra, as demonstrated by single-photon emission CT imaging.^447,448 In a study by Rordorf et al, 30 patients with acute ischemic events were treated with intravenous phenylephrine, which was titrated to improvement of neurological deficit, as demonstrated in 33% of the patients.^445,446 In this trial, patients were entered within 12 hours of the onset of symptoms but were excluded in the presence of recent or known cardiac ischemic events, congestive heart failure, intracerebral hemorrhage, or edema related to a completed infarction. Patients were maintained hypertensive for a period of 1 to 6 days, and neurological status at discharge was improved in those who had responded to the therapy. In other reports by Hillis et al, patients were randomized to induced hypertension or conventional management.^443,444 Serial DWI and PWI studies were performed before and during the period of induced hypertension. After 3 days of treatment, patients who were treated with induced hypertension showed an improvement in neurological examination, no change in DWI lesion volume, and reductions in PWI abnormality.

Wityk et al used induced hypertension for treatment of patients who were within 12 hours of onset of symptoms but who could not be treated with thrombolytic therapy.^449,450 They also advocated the use of DWI and PWI as a means to demonstrate improved perfusion to monitor such patients in an intensive care setting and when intervention is undertaken to achieve a target systolic blood pressure or mean arterial pressure of 20% to 30% above baseline. Other treatment options include withdrawing previous antihypertensive therapy, augmenting intravenous fluids, or starting intravenous phenylephrine. As part of the treatment paradigm, serial neurological examinations are performed to determine whether neurological improvement occurs; patients who show no improvement in a 30- to 60-minute period are considered nonresponders, and the intervention is stopped. Patients who have responded to this mode of therapy are maintained at that level and weaned according to neurological examination and functional imaging. Data demonstrating the safety and efficacy of this strategy are needed.

A. Carotid Endarterectomy

Little information exists about the effectiveness of surgical treatment of patients with acute ischemic stroke. Most cases of immediate operation are performed in the setting of an acute stroke after carotid endarterectomy. Emergency carotid endarterectomy generally is not performed in other settings of acute ischemic stroke because the risks of the procedure are perceived to be high. The sudden restoration of blood flow might increase the development of brain edema or lead to hemorrhagic transformation, especially among patients with major infarctions. In addition, the time required for detecting the arterial lesion and mobilizing the operating room limits the utility of surgery.

However, some surgeons report encouraging results from emergency operations for patients with severe stenosis or occlusion of the internal carotid artery existing for ≤24 hours.^{324,386,451–460} In general, improvement after surgery was found among patients with mild to moderate neurological impairments. Still, the data are limited, and the usefulness of urgent surgery among patients with severe neurological deficits is even less clear.

The indications for immediate carotid endarterectomy in a patient with an acute ipsilateral ischemic stroke and an intraluminal thrombus associated with an atherosclerotic plaque at the carotid bifurcation are controversial. The morbidity associated with surgery appears to be high among patients with an intraluminal thrombus demonstrated by cerebral angiography.^461–464 Although some groups report low rates of complications and good neurological outcomes with immediate surgery,^461–463 others have reported better results when the patients are treated initially with anticoagulants followed by delayed operation.⁴⁶⁴

B. Other Surgical Procedures

Immediate extracranial-intracranial arterial bypass for treatment of ischemic stroke failed to improve outcomes and was associated with a high risk of intracranial hemorrhage.⁴⁶⁵ However, some surgeons have reported favorable results with emergency bypass procedures.^466,467 In an occasional patient with an acute neurological deficit secondary to an embolus of the MCA, outcome might be improved by an emergency microsurgical embolectomy of the MCA.^468,469 Experience with immediate surgical procedures for treatment of acute ischemic stroke in the vertebrobasilar circulation is extremely limited.

C. Conclusions and Recommendations

Data on the safety and effectiveness of carotid endarterectomy and other operations for treatment of patients with acute ischemic stroke are not sufficient to permit a recommendation. Surgical procedures may have serious risks and may not favorably alter the outcome of the patient.

A. Angioplasty and Stenting

Limited data are available about the use of angioplasty and stenting in the emergency treatment of intracranial or extracranial lesions in patients with acute ischemic stroke.^474–476 Angioplasty and stenting have been used to treat patients with acute stroke secondary to carotid artery dissection.⁴⁷⁷ In one series, emergency angioplasty and stenting of the internal carotid artery were performed in conjunction with intra-arterial thrombolysis in 25 patients who had acute carotid artery occlusion with secondary artery-to-artery embolism to the MCA.⁴⁷⁸ Results were compared with another group of 25 patients who were treated medically; favorable outcomes were more frequent (56% versus 26%) among patients with endovascular treatment. Jovin et al⁴⁷⁹ were successful in achieving recanalization in 23 of 25 patients who had emergency stenting of the extracranial internal carotid artery. Brekenfeld et al⁴⁸⁰ treated 350 patients with intra-arterial urokinase and noted that recanalization could be increased with angioplasty and implantation of stents. Angioplasty with or without stenting has been combined with emergency administration of thrombolytic agents in patients with occlusions in the vertebrobasilar circulation.^481,482

B. Mechanical Clot Disruption

Noser et al⁴⁸³ treated 16 patients with occlusion of the MCA and 16 others with occlusion of the internal carotid artery with aggressive mechanical clot disruption. In most cases, the endovascular treatment was an adjunct to thrombolysis. A Swiss study of 350 patients treated with intra-arterial pharmacological thrombolysis found that mechanical fragmentation improved the success for recanalization.⁴⁸⁰ Berlis et al⁴⁸⁴ used an endovascular photoacoustic device to speed recanalization.

C. Clot Extraction

Devices have been used to extract thrombi from occluded intracranial arteries.^485,486 In the Mechanical Embolus Removal in Cerebral Embolism (MERCI) trial, vessels were opened with a device that removed the thrombus from an intracranial artery.^487–489 The device was associated with rapid opening of the artery, but the efficacy in recanalization and safety results achieved with the MERCI retrieval system were similar to those achieved with intra-arterial prourokinase in the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial.³³⁶ The rate of recanalization of the MCA in MERCI was 45%, and it was 66% in PROACT II. In MERCI, 17 patients also received thrombolytic medications when the device was unable to achieve recanalization, but the outcomes of these patients were not reported. Although the FDA has approved the use of the MERCI device for reopening intracranial arteries, its clinical utility has not been established.

D. Conclusions and Recommendations

The area of endovascular treatment of patients with acute ischemic stroke shows great promise. A number of techniques and devices are being studied. Already, the FDA has approved one device to extract a thrombus from an occluded intracranial artery. Other devices likely will be approved in the future. Emergency angioplasty also may achieve a role in management. As with the intra-arterial administration of thrombolytics, the use of these devices will be limited to those comprehensive stroke centers that have the resources and physician expertise to perform these procedures safely.

A. Combination of Thrombolysis and Neuroprotective Therapies

There have also been very limited studies of combination cytoprotective and reperfusion therapy in acute stroke (lubeluzole,⁴⁹⁴ hypothermia,⁴⁹⁵ magnesium,³¹ clomethiazole⁴⁹⁶). Until randomized clinical efficacy trials can be completed, combination reperfusion therapies for acute stroke will remain experimental for the foreseeable future.

B. Thrombolysis and Antiplatelet Agents

Use of platelet glycoprotein IIb/IIIa inhibitors has been suggested to prevent platelet activation and reocclusion and is being evaluated in several phase I studies as adjunctive therapy to intra-arterial thrombolysis. Other clinical trials of combination plasminogen activator and glycoprotein IIb/IIIa inhibitors, some based on perfusion brain imaging, are under way. Three recently completed studies^497–499 have suggested that intra-arterial administration of thrombolysis in combination with platelet glycoprotein IIb/IIIa inhibitors may be safe and may potentially improve outcome. A multicenter study⁴⁹⁷ reported the results of treating patients with acute vertebrobasilar occlusion using a combination of an intravenous bolus of abciximab (0.25 mg/kg) followed by 12-hour infusion therapy (0.125 μg/kg per minute) and intra-arterial rtPA in 47 patients. The results were compared with a retrospective cohort of 41 patients treated by intra-arterial rtPA monotherapy (median dosage, 40 mg). The rates of symptomatic intracranial hemorrhages were 13% and 12% for combination treatment and thrombolytic treatments, respectively. The combination treatment had higher rates of complete recanalization (45% versus 22%), favorable outcomes (34% versus 17%), and survival (62% versus 32%) compared with thrombolysis alone. A second study⁴⁹⁸ evaluated 26 patients with acute ischemic stroke (NIHSS score >10). Combined use of intravenous abciximab and intra-arterial urokinase thrombolysis in 10 patients was compared with intra-arterial urokinase alone in 16 patients. The recanalization rate was higher in the combined urokinase and abciximab group than in the urokinase group (90% versus 44%) with a trend of better functional outcome (50% versus 80%). No significant difference was noted in rates of symptomatic intracerebral hemorrhage (25% versus 30%). A prospective, nonrandomized, open-label trial⁵⁰⁰ was conducted to evaluate the safety of an escalating dose of reteplase in conjunction with intravenous abciximab in patients with acute ischemic stroke (3 to 6 hours after symptom onset) in 20 patients. The safety stopping rule was not activated in any of the tiers. One symptomatic intracerebral hemorrhage was observed in 1 of the 20 patients (1 U tier). Partial or complete recanalization was observed in 13 of the 20 patients. Thirteen patients demonstrated early neurological improvement, and favorable outcome at 1 month was observed in 6 patients.

C. Conclusions and Recommendations

The potential for combination interventions to restore perfusion to the brain given with or without neuroprotective therapies has great appeal. However, currently available data do not provide conclusive evidence for either the safety or efficacy of combinations of medications to improve cerebral perfusion. Data are limited with regard to the usefulness of mechanical devices to augment the effects of pharmacological thrombolysis to treat acute ischemic stroke. No data are available to demonstrate the efficacy of a neuroprotective intervention as a complement to thrombolysis or other therapies to restore perfusion.

Conclusions and Recommendations

Considerable experimental and clinical research is required before an intervention with identified neuroprotective effects can be recommended for treatment of patients with acute ischemic stroke. Several steps to improve research have been recommended.⁵⁸⁴ It is hoped that ongoing studies of neuroprotective interventions, including hypothermia, potentially tested alone or in combination with measures to restore perfusion, will demonstrate safety and efficacy.

A. Admission to the Hospital

Approximately 25% of patients may have neurological worsening during the first 24 to 48 hours after stroke. It is difficult to predict which patients will deteriorate.^{277,585–588} Besides progression of the initial stroke, the potential for preventable neurological or medical complications also means that patients with stroke should be admitted to the hospital in most circumstances.^589–593 The goals of treatment after admission to the hospital are to (1) observe for changes in the patient’s condition that might prompt initiation of medical or surgical interventions, (2) provide observation and treatment to reduce the likelihood of bleeding complications after the use of rtPA, (3) facilitate medical or surgical measures aimed at improving outcome after stroke, (4) begin measures to prevent subacute complications, (5) plan for long-term therapies to prevent recurrent stroke, and (6) start efforts to restore neurological function through rehabilitation and good supportive care.

B. Specialized Stroke Care Units

Several studies, performed mainly in Europe, demonstrate the utility of comprehensive stroke units in lessening the rates of mortality and morbidity after stroke.^594–606 The positive effects can persist for years. The benefits from treatment in a stroke unit are comparable to the effects achieved with intravenous administration of rtPA.⁶⁰⁷ In addition, stroke unit care can be given to a broad number of patients regardless of the interval from stroke or severity of the neurological impairments, including patients who cannot be treated with thrombolytic therapy. In general, a European stroke unit includes a geographically defined facility staffed by skilled professionals, including physicians, nurses, and rehabilitation personnel. The unit may have monitoring capabilities to permit close observation of changes in patients’ neurological status or medical complications.^608,609 European stroke units usually do not include intensive care unit–level treatment, including ventilatory assistance. Regular communications and coordinated care also are key aspects of the unit. Standardized stroke orders or integrated stroke pathways improve adherence to best practices for treatment of patients with stroke.^610–612

Such specialized care is included in recommendations for a CSC. It should be noted that most stroke units in the United States have much shorter lengths of stay than do the units evaluated in the European studies, and most do not incorporate comprehensive rehabilitation care.

C. Deep Vein Thrombosis and Pulmonary Embolism

Pulmonary embolism accounts for ≈10% of deaths after stroke, and the complication may be detected in ≈1% of patients who have had a stroke.⁶³⁷ Pulmonary emboli generally arise from venous thrombi that develop in a paralyzed lower extremity or pelvis. Besides being associated with a life-threatening pulmonary event, symptomatic deep vein thrombosis also slows recovery and rehabilitation after stroke. The risk of deep vein thrombosis is highest among immobilized and older patients with severe stroke.^638–642

The institution of measures to prevent deep vein thrombosis after stroke is a quality indicator for stroke centers in the United States.^643,644 The options for lowering the risk of deep vein thrombosis include early mobilization, antithrombotic agents, and the use of external compression devices. The benefit of early mobilization is described above. Anticoagulants are given to prevent deep vein thrombosis and pulmonary embolism among seriously ill patients. Much of the support for the use of anticoagulants comes from clinical studies testing these agents in treating bedridden patients other than those with stroke.^645,646 Meta-analysis demonstrated that these medications were effective among patients with stroke.⁶⁴⁷ Several clinical trials have demonstrated the utility of heparin and the LMW heparins in preventing deep vein thrombosis. There does not appear to be a significant difference in efficacy or safety between unfractionated heparin and the LMW heparins.^648–660 The risk of serious bleeding complications seems to be relatively low.⁶⁵⁴ Long-term treatment usually involves the use of oral anticoagulants such as warfarin. Ridker et al⁶⁶¹ found that low-intensity warfarin therapy was effective in preventing recurrent venous thromboembolism. Ximelagatran also appears to be effective in lowering the risk of deep vein thrombosis, but this agent is not yet available in the United States. Aspirin also may be effective for patients who have contraindications to anticoagulants, although direct comparisons with anticoagulants are not available.^662,663 Experience with the use of external compression of the veins in the lower extremities such as stockings or alternating pressure devices is limited.^664–666 External compression may be useful for managing patients who cannot be treated with antithrombotic agents.^654,655 Patients with pulmonary embolism from thrombi in the lower extremities and a contraindication for antithrombotic treatment may need the placement of a device to occlude the inferior vena cava.

D. Conclusions and Recommendations

The management of patients after admission to the hospital remains a key component of overall treatment, and it is as important as the acutely administered therapies. The components of this aspect of treatment dovetail with the acute interventions to restore perfusion. In addition, these components of management can be given to the large number of patients who are not eligible for treatment with the acutely administered interventions. These therapies can improve outcomes by lessening complications and speeding recovery from stroke.

A. Ischemic Brain Swelling

Brain swelling, when associated with astrocytic ischemia, is due to a cytotoxic reaction mediated by multiple factors, including free radicals.⁶⁶⁸ Progressive clinical deterioration due to swelling from MCA occlusion is seen more often in women and in patients with additional vascular territorial infarctions on initial CT.⁶⁶⁹ Brain swelling typically occurs in patients who have had an occlusion of the stem of the MCA and appears ≈4 days after the onset.^670–674 Dramatic early swelling has been described and attributed to reperfusion edema and possibly effects of rtPA. The term malignant has been affixed to brain swelling to delineate a group of patients with a large territorial infarct that swells within 24 hours, causing brain herniation signs.⁶⁷⁵ The proportion of patients with this so-called malignant form is unknown, and its clinical profile is not well defined. Rapid deterioration from cerebellar infarcts with swelling is also more common and may be associated with sudden apnea from brain stem compression and cardiac arrhythmias. The overall risk of brain swelling in patients with anterior circulation ischemic stroke is low and is estimated to be 10% to 20%.^376,377 The incidence in posterior circulation stroke is unknown. An imaging study may predict deterioration from swelling. Early CT scan hypodensity, defined as <12 hours after onset, of >50% of the MCA territory and the presence of hyperdense MCA signs were independent predictors of neurological deterioration.⁶⁷¹ In addition, patients with MCA infarction who developed a mass effect on CT scan as identified by compression of the frontal horn, shift of the septum pellucidum, and, later, shift of the pineal gland are at risk of worsening clinically and developing clinical signs of brain herniation.⁶⁷¹ Perfusion CT scan performed within 6 hours of symptom onset could determine which patient would deteriorate from swelling. Large hypoattenuation (defined as greater than two thirds of the MCA territory) on enhanced CT and large hypoperfusion on CT perfusion maps predicted development of “malignant MCA infarct” with high sensitivity of 91% and specificity of 94%.⁶⁷⁶

Very few clinical signs predict clinical deterioration. Patients with bilateral ptosis and involvement of the nondominant hemisphere may be at a higher risk. Multivariable analysis found that a history of hypertension, history of heart failure, presence of elevated white blood cell count, presence of >50% MCA hypodensity, and involvement of additional vascular territory increased the development of fatal brain edema.⁶⁷⁷ The need for early mechanical ventilation increases the risk of death.⁶⁷⁸

In patients with MCA infarctions who develop brain edema, increased intracranial pressure probably occurs late in the course, if at all.⁶⁷⁹ Therefore, aggressive management of intracranial pressure in patients with early developing cerebral edema is not an established goal. One of the principles in the management of brain edema after MCA infarction is to prevent further deterioration from tissue displacement and brain stem shift.

Similarly, management of cerebellar swelling should include a decompressive suboccipital craniotomy to remove the necrotic tissue. Initial management of brain swelling should include restriction of free water to avoid hypo-osmolar fluid that may worsen edema. Factors that could exacerbate swelling such as hypoxemia, hypercarbia, and hyperthermia should be corrected. The head of the bed can be elevated at 20° to 30° in an attempt to help venous drainage. Antihypertensive agents, particularly those that include cerebral vasodilatation, should be avoided.

The treatment of patients with raised intracranial pressure, present at a late stage, is directed toward standard measures that include hyperventilation, osmotic diuretics, drainage of cerebral fluid, or decompressive surgery.⁶⁸⁰ No clinical trials address the efficacy of any of these aggressive management strategies after stroke. No evidence indicates that hyperventilation, corticosteroids in conventional or large doses, furosemide, mannitol, or glycerol or other measures that reduce intracranial pressure improve outcome in patients with ischemic brain swelling.^681–690 Mannitol is typically used at 0.25 to 0.5 g/kg IV administered over 20 minutes, lowers intracranial pressure, and can be given every 6 hours.⁶⁹¹ The usual maximal dose is 2 g/kg. The effect of mannitol in patients with ischemic brain swelling is unknown, but it is often used as a temporizing measure before patients undergo decompressive craniectomy. Despite intensive medical management, the death rate is estimated to be as high as 50% to 70%.^465,466

Decompressive surgery, including hemicraniectomy and durotomy with temporal lobe resection, remains the most attractive option for ischemic brain swelling.^692–701 Timing of surgery is poorly defined, with some opting for early (within 24 hours) intervention.⁷⁰² Recent studies have found that decompressive craniectomy may have a less favorable outcome than suggested.⁷⁰³ More disability may be expected in older patients (>55 years of age) and in patients with dominant infarctions.⁷⁰⁴ Additional surgery, “strokectomy,” of parts of the frontal or temporal lobe may be needed in younger patients who fail to improve.⁷⁰⁵ The timing of decompressive hemicraniectomy and indications remain unclear. Several randomized, controlled clinical trials are under way in Europe.⁷⁰⁶ An alternative option to control brain swelling is moderate hypothermia, defined as 33°C to 34°C, with the use of noninvasive or invasive cooling devices; this strategy is unproven, but feasibility trials are under way.

Patients with cerebellar infarct often develop acute hydrocephalus. If hydrocephalus is present, drainage of cerebral fluid through an intraventricular catheter can rapidly lower intracranial pressure; however, a concern about upward herniation of cerebellar tissue remains.^707–710 Suboccipital craniotomy is the treatment to relieve both hydrocephalus and brain stem compression caused by large cerebellar infarctions.^{703,698,710–716}

B. Hemorrhagic Transformation

Considerable information exists about the natural rate of early hemorrhagic transformation of ischemic stroke.^717–723 Some studies suggest that almost all infarctions have some element of petechial hemorrhage. With the use of CT, one prospective study estimated that ≈5% of infarctions spontaneously developed symptomatic hemorrhagic transformations from frank hematomas.⁷²⁴ The location, size, and cause of stroke can influence the development of this complication. Further information about the influence of hemorrhagic transformation outcome in stroke is needed. Small asymptomatic petechiae are much less important than hematomas, which can be associated with neurological decline. The use of all antithrombotics, but especially anticoagulants and thrombolytic agents, increases the likelihood of serious hemorrhagic transformation.^{279,725–727} The early use of aspirin is also associated with a small increase in the risk of clinical detectable hemorrhage.

Management of patients with hemorrhagic infarction depends on the amount of bleeding and its symptoms and may include clot evacuation in deteriorating patients. A recent study found that hemorrhagic transformation in stroke patients was detected in one third of patients admitted to acute rehabilitation, but functional outcome was not significantly different from that of patients who did not have hemorrhagic transformation on the first CT scan.⁷²⁸ Hemorrhagic conversion in patients with cerebellar infarct significantly increased the risk of deterioration.⁷²⁹ Recently, it has been suggested that gadolinium enhancement on T1-weighted MR images is predictive of hemorrhagic transformation, but this finding is unconfirmed.⁷³⁰

C. Seizures

The reported frequency of seizures during the first days of stroke ranges from 2% to 23% depending on study designs.^{704,731–734} The true risk of seizures appears to be toward the lower end of the estimate. Seizures are more likely to occur within 24 hours of stroke and are usually partial, with or without secondary generalization. Recurrent seizures develop in ≈20% to 80% of patients; however, recent estimates have found the rate of early postischemic stroke seizures to range from 2% to 33%. Late seizures vary from 3% to 67%.^735,736 The risk of late seizures is higher in patients with preexisting dementia.⁷³⁷ Status epilepticus is uncommon.⁷³⁸ No data are available on the utility of prophylactic administration of anticonvulsants after stroke. Few data are available on the efficacy of anticonvulsants in the treatment of stroke patients who have experienced seizures. Thus, recommendations are based on the established management of seizures that may complicate any neurological illness.

D. Conclusions and Recommendations

Considerable research is needed on the prevention and treatment of neurological complications of acute ischemic stroke, including seizures, hemorrhagic transformation of the infarction, and brain edema. The latter, which is a leading cause of death after a major ischemic stroke, is a pressing issue. At present, neither medical nor surgical interventions have been established as effective in controlling brain edema, preventing the neurological consequences of increased intracranial pressure or herniation, or improving outcomes after stroke. Although several medical interventions are used traditionally to control edema and although surgical procedures may be a life-saving measure, it appears that earlier interventions may be associated with better clinical outcomes than waiting for the patient to have signs of profound neurological dysfunction, such as herniation. Until additional data are available, the recommendations that follow are based on general consensus or limited information.

E. Palliative Care

Unfortunately, some patients with stroke have a fatal brain injury. These critically ill persons have profound neurological impairments such as a persistent vegetative state or evidence of unstable vital signs. Other patients with stroke have serious preexisting medical or neurological illnesses, such as dementia, that have caused severe impairments, and the new cerebrovascular event may add more disability. Despite the interventions that are described in this outline, the prognosis of such patients often is very poor. Many people would not want to survive if a devastating stroke would lead to a persistent vegetative state or other condition of devastating incapacity.

An increasing number of patients have advanced directive statements that provide instructions about emergency treatment in a situation such as a massive stroke. Physicians should honor those directives. In other circumstances, such directives may not be available, and the patient’s neurological status usually precludes decision making. Occasionally, a guardian with medical power of attorney can make the decision. Otherwise, the physician should involve family members. The physician should provide clear information about the nature of the stroke, the prognosis, and the treatment options. The family should be given the opportunity to select or withhold medical interventions. In such situation, the medical care may emphasize measures to keep the patient comfortable and to support the family during the terminal aspects of the stroke.