Intra-arterial Thrombolysis
Direct infusion of thrombolytic agents into occluded blood vessels is a potential alternative or adjunct to therapy with intravenous rt-PA [see Figure 7]. The value of intra-arterial thromboly-sis has been demonstrated with the experimental agent prourokinase (Prolyse), which is the highly clot-specific precursor of urokinase. The Prolyse in Acute Cerebral Thromboem-bolism (ProACT) trial enrolled patients with ischemic stroke caused by middle cerebral artery (MCA) occlusion within 6 hours of onset.23 Eligibility criteria were similar to those for intravenous rt-PA treatment. Patients underwent emergent angiogra-phy; if MCA occlusion was confirmed, either intra-arterial prourokinase (9 mg) or placebo was infused for 2 hours. All patients received concomitant intravenous heparin. Arterial occlusions effectively opened in 67% of patients given prourokinase, whereas only 18% opened in patients given placebo. Three months after stroke, 40% of treated patients were functionally independent, compared with 25% of those given placebo (P = 0.04). The drug seemed particularly effective for moderately severe strokes. Symptomatic intracerebral hemorrhage occurred in 10.2% of treated patients, compared with 1.8% of those given placebo.
Because prourokinase is not commercially available, many centers that are capable of performing intra-arterial thromboly-sis are using rt-PA, although it is not approved for this purpose. The intra-arterial rt-PA dose is uncertain, though many centers use 0.2 mg/kg (maximum, 20 mg), and all other aspects of the ProACT protocol may be followed.
Table 3 Indications and Contraindications for Intravenous rt-PA Treatment in Acute Ischemic Stroke
|
Indications |
Contraindications |
|
|
Absolute |
Relative |
|
|
Clinical diagnosis of disabling stroke firmly established |
Onset > 3 hr ago or patient not seen normal within previous 3 hr |
Glucose < 50 or > 400 mg/dl |
|
Seizure at stroke onset |
||
|
Patient > 17 yr |
Intracranial mass lesion or hemorrhage on noncon-trast head CT |
Major surgery within 14 days |
|
Onset of symptoms or last time seen |
Arterial puncture at a noncompressible site or LP within 1 wk |
|
|
normal < 3 hr ago |
Previous stroke or serious head trauma within previous 3 mo |
|
|
Previously independent functional status |
Rapidly improving symptoms suggestive of TIA |
|
|
Any history of intracranial hemorrhage |
r j r o . r oo GI or GU hemorrhage within 21 days |
|
|
Current use of anticoagulants with PT > 15 sec or use of heparin within the past 48 hr* |
||
|
Platelets < 100,000/mm3 |
||
|
Presenting symptoms suggestive of subarachnoid hemorrhage (worst headache of patient’s life) |
||
|
Blood pressure > 185/110 mm Hg unless minimal doses of a smooth-acting I.V. agent such as la-betalol were sufficient to lower below this range+ |
||
|
Previously known cerebral aneurysm or arteriove-nous malformation |
||
*Partial thromboplastin time and PT results are not needed before therapy unless patient is on anticoagulants.
t Caution: Do not lower blood pressure acutely by more than 10% to 15% and avoid agents that precipitously lower blood pressure. A patient who requires multiple doses should be excluded. After I.V. rt-PA is administered, blood pressure must be kept below 185/110 mm Hg for at least 24 hours. CT—computed tomography GI—gastrointestinal GU—genitourinary LP—lumbar puncture PT—prothrombin time rt-PA—recombinant tissue plasminogen activator TIA—transient ischemic attack
Figure 7 Intra-arterial thrombolysis for acute ischemic stroke. Four hours after onset of left hemiparesis and neglect, conventional angiography (lateral view shown) revealed acute occlusion of the middle cerebral artery (MCA) (a). After treatment with intra-arterial thrombolysis, the MCA recanalized (b) and the patient had near-complete recovery from the deficit.
The role of intra-arterial thrombolysis in other cerebral vessels remains uncertain. Cases of spectacular responses to throm-bolytics have been reported in patients with basilar occlusion, even well beyond 6 hours. Although it is claimed that the brain stem may be relatively more tolerant of ischemia and less susceptible to hemorrhage, this hypothesis remains to be proved.
Combinations of intravenous and intra-arterial thromboly-sis,24 as well as mechanical manipulation or retrieval of an acute thrombus, are currently under investigation.
Neuroprotection
Neuroprotective strategies involve interfering with the is-chemic cascade, thereby prolonging cellular viability and substantially reducing stroke size. Regrettably, a number of different compounds that seemed effective in animal studies failed in human clinical trials.25 While several agents are being developed, researchers are attempting to determine how best to simulate stroke in animals so that animal data will be more generaliz-able to humans.
Supportive Medical Management
Several general medical issues are important for all stroke patients, including management of airway and oxygenation, blood pressure and hemodynamics, blood glucose, and temperature. Medical complications are also common after stroke, and such complications are associated with poor outcomes.26 Management of these common issues and complications is critically important. Therefore, it is advisable to treat stroke patients in dedicated stroke units to reduce morbidity, mortality, and disability.27
Respiration Respiratory function must be evaluated immediately in all stroke patients. Ventilatory drive is usually intact except after medullary or massive hemispheric infarction or hemorrhage. The ability to protect the airway from aspiration may also be impaired, particularly in the acute setting. Intubation and mechanical ventilation may be necessary in these pa-tients.28 Most stroke patients do not require such aggressive maneuvers, but supplemental oxygen should be provided to maintain oxygen saturation above 95%.29
Blood pressure Maintenance of adequate blood pressure is vital for all patients. Cerebral blood flow to ischemic regions is dependent on cerebral perfusion pressure, which in turn is determined by the difference between mean arterial pressure and intracranial pressure (ICP). Elevated blood pressure is common at the time of initial stroke presentation, even in patients without chronic hypertension. Rapid lowering of blood pressure may further impair cerebral blood flow and worsen the ischemic in-jury.30 Elevations in blood pressure will often spontaneously and gradually improve during the first few days after stroke.
Antihypertensive therapy is indicated before and during thrombolysis with rt-PA; when infarction converts to hemorrhage; and in patients with myocardial ischemia, aortic dissection, or hypertensive encephalopathy. Candidates for thrombol-ysis should be treated only with modest measures (e.g., topical nitropaste or small intravenous boluses of labetalol) to maintain blood pressure below 185/110 mm Hg. Definitive treatment— including intravenous infusions of nicardipine, labetalol, or sodium nitroprusside—is appropriate for the other indications.
Fluid volume Careful volume replacement in patients with acute stroke improves cardiac output and cerebral perfusion.31 Patients should receive isotonic saline to maintain euvolemia. Additional fluid administration (hypervolemic hemodilution) may increase cerebral blood flow while reducing blood viscosity without causing a reduction in oxygen delivery. However, clinical trials of hemodilution have yielded mixed results, with the largest of these trials showing no benefit.32 Further investigation is required before hemodilution can be advocated.
Temperature Brain and body temperatures play an important role in outcome after stroke. Hypothermia improves outcome after ischemic injury in animals, after cardiac arrest, and after cardiac and neurosurgical procedures in humans, but it has not been adequately studied in acute stroke. Hypothermia may mitigate neurotransmitter toxicity, reduce neuronal metabolic demands, and improve cerebral edema in acute stroke.33 On the other hand, fever or even mild hyperthermia is known to be deleterious.34 An elevation in body temperature dramatically increases the odds of severe disability or death, with risk doubling for each 1° C (1.8° F) above normal.35 Normothermia should be maintained with antipyretics or cooling blankets, but therapeutic hypothermia must undergo more investigation before it can be recommended for focal ischemia.
Blood glucose levels Hyperglycemia appears to correlate with poor outcome in stroke.36 Glucose may be metabolized to lactic acid, resulting in acidosis and increased tissue injury. Although the effect of correcting the blood glucose level is unknown, normalization is recommended. The administration of parenteral glucose should be minimized in patients with acute stroke.
Intracranial pressure In the most critically ill stroke patients, cerebral edema and elevations in ICP may complicate the clinical course. The expanding infarction may cause both focal and diffuse effects that typically peak at 2 to 5 days.37,38 Large hemispheric stroke may result in malignant MCA syndrome, in which the edematous infarcted tissue compresses the anterior and posterior cerebral arteries, resulting in secondary infarctions.37 Similarly, infarction of the cerebellum may lead to basilar artery compression and brain stem ischemia. Mortality in both malignant MCA syndrome and cerebellar infarction approaches 80% [see Intracerebral Hemorrhage, below]. Surgical decompression has a potential role in a minority of stroke patients. In acute cerebellar stroke, cran-iotomy with cerebellar resection is a lifesaving intervention that has become widely accepted.39 Surgery removes the mass effect and prevents secondary brain stem and vascular compression. Malignant MCA syndrome may be similarly amenable to hemi-craniectomy; this controversial approach is under investigation.
Preventive measures Prophylaxis for deep vein thrombosis should be instituted early with heparin (5,000 units given subcu-taneously every 12 hours)15 [see 1:XVIII Venous Thromboembolism]. For patients in whom heparin is contraindicated (e.g., patients with acute hemorrhage), pneumatic compression stockings are employed. Similarly, prevention of aspiration pneumonia should be a priority from the initial presentation at the hospital. Early intervention with physical therapy, occupational therapy, and speech therapy is important in recovery and prevention of complications.
Pognosis and recovery
Initial stroke severity is one of the strongest predictors of out-come,35 and early evidence of improvement is a good prognostic sign.40 Recovery also depends on the size and location of the infarction or hemorrhage. Small infarctions, particularly subcortical lacunar strokes, may result in little chronic deficit, whereas large cortical infarctions may cause severe, permanent disability. Co-morbid diseases, such as hypertension and diabetes, do not appear to affect recovery, but younger patients have a better prognosis than older patients.40 Despite these predictors, the marked variability among patients makes early prognostication difficult. In general, recovery is greatest in the first 3 months after stroke.
The mechanisms of recovery after stroke remain poorly understood. Infarcted brain tissue is irreparable, so recovery of function has long been presumed to occur by recruitment of other neurons to serve new or additional roles. In rodents, neurons may be influenced to create new synapses after stroke.41 Electrical brain mapping in monkeys has demonstrated that the cerebral cortex can be functionally reorganized during recovery after an infarction.42 Similarly, functional MRI in humans has shown that activity in both hemispheres increases as patients improve, suggesting recruitment of neighboring cortex, as well as recruitment of the corresponding area of the contralateral cortex.43
Table 4 Modifiable Risk Factors for Stroke
|
Risk Factor |
Prevention |
Risk-Reduction Potential |
Clinical Trial Evidence? |
|
Hypertension |
P, S |
25%-47% |
Yes |
|
Tobacco |
P, S |
? |
No |
|
Hyperlipidemia |
P, S |
24%-31% |
Yes |
|
Diabetes |
P |
? |
No |
|
Alcohol |
P |
50% |
No |
|
Exercise |
P, S |
? |
No |
|
Homocystine or |
P, S |
? |
No |
|
homocysteine |
|||
|
Infection |
P |
? |
No |
|
Atrial fibrillation |
P, S |
68% |
Yes |
|
Symptomatic carotid |
S |
65% |
Yes |
|
stenosis > 70%* |
|||
|
Asymptomatic carotid |
S |
53% |
Yes |
|
stenosis > 60%+ |
*Two-year absolute risk reduction of 17%.
+Five-year absolute risk reduction of 6%.
P—primary
S—secondary
Recovery may be improved by inducing these restorative mechanisms. Physical, occupational, and speech therapy are widely used, but no consensus exists regarding the optimal approach or timing of intervention. Neurotrophic growth factors and amphetamines may stimulate neuronal sprouting and also accelerate recovery by increasing the activity of uninjured neu-rons.41 However, these pharmacologic approaches require extensive research before they can be advocated for routine use in stroke rehabilitation.
Ischemic stroke prevention
Reduction of Risk Factors
Numerous risk factors for stroke are modifiable. Reduction of factors such as excessive alcohol consumption, tobacco use, hypertension, and diabetes, as well as aggressive lipid control, contributes to stroke prevention [see Table 4].
Hypertension Hypertension has the highest population-attributable risk of any of the modifiable risk factors for stroke, and reduction in blood pressure has been shown to dramatically reduce stroke risk.44 The reduction in risk of first stroke for those treated with antihypertensive agents is 25% to 47%.45 Both dia-stolic and systolic hypertension have been linked to excess risk of stroke. Reducing isolated systolic hypertension even in the elderly has been shown to markedly lower stroke rates.46 Patients who are undertreated with antihypertensive agents still have a higher stroke rate than those who are adequately treated.47 Recommended actions to reduce the risk of stroke include (1) maintaining blood pressure below 140/90 mm Hg, (2) frequent checking of patients’ blood pressure by physicians, and (3) at-home monitoring of blood pressure by patients.44 Lowering di-astolic blood pressure by 5 to 6 mm Hg can reduce stroke risk by 42%44; thus, hypertension should be assiduously diagnosed and treated. In the primary prevention of stroke and other major vascular events, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed that the thiazide diuretic chlorthalidone was effective and safe, and it is also inexpensive.48 Comprehensive discussion about the management of hypertension for primary prevention is provided elsewhere [see 1:III Hypertension].
Although many antihypertensive agents can effectively reduce blood pressure, drugs that act upon the renin-angiotensin system appear to have a unique role in both primary and secondary stroke prevention. Two major studies demonstrated that angiotensin-converting enzyme (ACE) inhibitors—specifically, ramipril used alone49 or perindopril used in combination with the diuretic indapamide50—reduce the risk of recurrent stroke by 25% to 30%. Furthermore, patients without a history of hypertension also seemed to benefit from the addition of an ACE inhibitor to their preventive regimen. A similar effect may exist for angiotensin receptor blockers (ARBs). In a trial comparing the beta blocker atenolol with the ARB losartan in patients with hypertension and left ventricular hypertrophy, there was a 25% reduction in the relative risk of a first stroke with the ARB.51 In these trials, ACE inhibitors and ARBs appeared to decrease the risk of stroke more than would be expected by their relatively modest lowering of blood pressure; this suggests the possibility of an additional beneficial action via an uncertain mechanism.
Tobacco use Daily cigarette smoking has been shown to increase the risk of stroke by 250%.52 A dose-effect response is seen in most studies. For those who smoke less than one pack a day, quitting reduces their risk to baseline within 5 years. For heavy smokers, the risk is greatly reduced but remains higher than that in individuals who never smoked. Switching from cigarettes to a pipe or cigars does not reduce stroke risk.
Hyperlipidemia Evidence has emerged implicating hyper-lipidemia as an independent risk factor for stroke, and studies have demonstrated impressive stroke risk reductions with statin agents. The Medical Research Council/British Heart Foundation Heart Protection Study (HPS), which included over 20,500 persons at high risk for coronary artery disease but who had characteristics that excluded them from previous statin studies, showed that long-term treatment with simvastatin (i.e., 40 mg daily for more than 5 years) reduced all strokes by 27%.54 The study included patients with total cholesterol levels of 135 mg/dl or more; benefits were apparent even in patients with normal total cholesterol levels.
In an older study of patients who had had a previous my-ocardial infarction and whose cholesterol level was lower than 240 mg/dl, those given pravastatin had a 31% reduction in the risk of stroke, compared with patients given placebo.55 In a study involving patients who had a median cholesterol level of 218 mg/dl and who received pravastatin, the relative risk reduction of stroke was 19%.56 Meta-analyses also suggest that the use of statins reduces the risk of first stroke by 24% to 29%.57,58 High-density lipoprotein cholesterol may be especially important in the risk of stroke. Statins may also exert their protective effects through mechanisms other than pure regulation of serum lipid concentrations. These effects include the processes involved in inflammation and thrombosis. In addition to pravastatin, sim-vastatin has an FDA indication for stroke prevention in patients with coronary artery disease and elevated cholesterol levels. Gemfibrozil was found to modestly reduce stroke in patients with coronary artery disease.59
Diabetes Although diabetes mellitus is a well-recognized risk factor for stroke, not all features of diabetes appear to contribute equally to that risk. Treatment of elevations in blood pressure and serum lipid levels appears to be more effective in reducing the risk of stroke, whereas treatment of hyperglycemia reduces the risk of microvascular complications.60 At present, no studies directly link glucose control with reduction in risk of stroke. However, the international Action in Diabetes and Vascular Disease (ADVANCE) study is examining the effects of controlling blood pressure and blood glucose in patients with type 2 diabetes mellitus.
Alcohol consumption In a quadratic model of the risk of stroke, there appears to be a J-shaped relation between alcohol intake and risk. In one report, those who consumed more than six drinks a day were at increased risk for stroke; those who consumed one to two drinks a day appeared to benefit from a protective effect of alcohol that reduced the risk of stroke by almost 50%.62 There did not appear to be a difference associated with the type of alcoholic beverage consumed (i.e., wine, beer, or liquor). In another report, drinking as little as one alcoholic drink a week reduced the risk of stroke by 22%, compared with drinking no alcohol.
Homocysteine level Elevated homocysteine levels are an independent risk factor for stroke.64 Trials of high doses of vitamins B6, B12, and folic acid demonstrated that these agents can reduce homocysteine levels, but their use had no significant impact on stroke risk. Because vitamin supplementation is inexpensive and readily available, some clinicians use this approach empirically, though fortification of the United States food supply with folic acid may obviate this practice.
Exercise Data from the Physician Health Study, a prospective cohort study of 21,823 men, demonstrated that exercise significantly reduced the risk of stroke, most likely by reducing other risk factors, including hypertension, lipid levels, and diabetes.
Infection Infection and inflammation may be the single most important area of stroke research in the next decade. There have been several observations linking infection and inflammation with stroke. People with poor dentition seem to have a higher incidence of stroke. Although this increase may be related to other risk factors and access to care, it may also be related to oral infections. Chlamydophila (formerly Chlamydia) pneumoni-ae titers may be an independent risk factor for stroke.67 Chlamy-dophila seems to promote thrombosis through effects on fibrino-gen and vascular endothelium.
