Treatment of Acute Stroke :Recommendations for Clinical Practitioners

doi:10.5214/135

Annals of Neurosciences, Vol 12, No 2 (2005)

Annals of Neurosciences, Volume 12, Issue 2 (April), 2005

Original Article

TREATMENT OF ACUTE STROKE: RECOMMENDATIONS FOR CLINICAL PRACTITIONERS

Mukul Varma

M.D.,D.M. Senior Consultant Neurologist
Indraprastha Apollo Hospitals, New Delhi

Abstract

Stroke is the second leading cause of death and disability worldwide. Moreover, it is expected that in developing countries the incidence of stroke will rise considerably during the next fifty years. About 80% of strokes are ischemic. Early treatment improves outcome. Treatment can begin at home itself immediately after the brain attack, by administering 325mg of aspirin if there are no clinical features suggesting intracerebral hemorrhage (ICH). Intravenous tissue plasminogen activator (tPA) remains the best hope of an excellent outcome in patients of acute ischemic stroke when administered within 3 hours of stroke onset. Timeliness and strict adherence to the NINDS protocol are the keys to its safe and effective use. There is a pressing need to educate people to recognize symptoms of stroke and reach a hospital immediately, as the majority of patients reach the hospital after the 3 hour window, and are unable to take advantage of this now proven therapy. The secret of survival and reduced morbidity in acute ischemic or hemorrhagic stroke however, lies in close monitoring and maintainence of the patient's vitals and internal milieu, and in measures to prevent and treat complications early. Reactive hypertension, particularly in acute ischemic stroke, may have a protective role, and except in certain situations discussed, should not be aggressively treated.

Key words: Stroke, Cerebrovascular disease, Acute treatment of stroke.

Introduction

Stroke is the second most common cause of acquired disability and the second leading cause of death in adults worldwide. (Bergen DC. 1996) Although the frequency of stroke and mortality due to stroke has declined in many industrialized countries probably due to improved awareness and treatment of risk factors, it is expected that the incidence of stroke will increase considerably in developing countries over the next fifty years, because with ageing of the population and improved treatment of heart disease, the number of persons at the highest risk of stroke will grow. Effective prevention and treatment of stroke can reduce death and suffering and cut down expenses due to healthcare and lost productivity.

Brain Attack

Neurologists now refer to a stroke as a "brain attack". This term conveys an urgency similar to that felt in a 'heart attack' and emphasizes that rapid diagnosis, evaluation and treatment is paramount in favorably influencing prognosis. Approximately eighty percent of strokes are ischemic in nature. Symptoms of ischemic stroke appear when neurons in the territory of an occluded vessel begin to malfunction due to a fall in cerebral blood flow. With further reduction in blood flow neurons suffer irreversible injury and the extent of this damage depends on the degree and duration of hypoperfusion. The region of cerebral tissue that is hypoperfused and "stunned" yet not irreversibly injured is called the #ofischemic penumbra#cf. The concept that "time is brain" emphasizes that stroke is a progressive disease and with each passing minute more neurons will die. Early action which may dissolve the clot, recanalize the occluded artery and restore blood flow to the ischemic penumbra can revive injured neurons and reverse deficit and prevent complications.

Treatment of Acute Ischemic Stroke

Aspirin

Aspirin 325mg PO can be given by a general practicioner at home itself if there are no clinical features suggesting hemorrhage. These include early and prolonged loss of consciousness, prominent headache, nausea and vomiting, extremely high blood pressure and neck rigidity. In this situation it is prudent to wait for an urgent non-contrast cranial CT scan to rule out hemorrhage before administering aspirin.

Intravenous Thrombolysis

NIH Stroke Scale

The need for rapid management of patients with acute ischemic stroke (AIS) means that a detailed neurologic examination is not practical in the emergency setting. Instead, a basic syndrome based knowledge of neuroanatomy is required. In keeping with this, the National Institutes of Health Stroke Scale (NIHSS) was developed (Fig. 1). This tool assesses the range of neurologic function including level of arousal; neglect; language; cranial nerves; and motor, sensory, and cerebellar function that in most cases can be performed in less than 5 minutes and can provide rapid quantitative reproducible and valid assessment of stroke severity. A low NIHSS score indicates a mild stroke and a high score indicates a severe stroke. Patients who present within 24 hours of stroke onset with NIHSS #mt 15 have a poor prognosis if they receive no acute therapy,. Patients with a baseline score #mt 20 have higher incidence of intracranial hemorrhage with intravenous thrombolytic therapy (tPA), but still fare better than patients with a score #mt 20 who do not receive tPA. ( Adams et al. 2003, Schlegel et al. 2004.)

Intravenous Thrombolytic Therapy

If hemorrhage is ruled out by an immediate non-contrast CT scan, and less than 3 hours have elapsed since onset of symptoms, intravenous thrombolysis is the treatment of choice. Thrombolytic medication has the potential to dissolve the clot, recanalize the occluded artery, and restore blood flow to the ischemic penumbra. Tissue plasminogen activator (tPA) is the only proven US Food and Drug Administration (FDA)-approved thrombolytic agent for acute ischemic stroke.

The National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study demonstrated that tPA given within 3 hours of symptom onset improved the chances of an excellent outcome (minimal or no disability) by 30% to 50% compared with placebo treatment, without any increase in mortality (NINDS rt-PA Stroke Study Group, 1995) Although patients who received tPA in the trial had a 6.4% chance of developing intracerebral hemorrhage (ICH) associated with neurologic worsening as compared with a rate of only 0.6% in those who received placebo, the rate of death from all other stroke-related causes was 9% in patients treated with tPA compared with 20% of those treated with placebo. Thus the benefit is clearly greater than the risk, making IV tPA an acceptable treatment within 3 hours of stroke onset. It may be noted that IV tPA has been shown to benefit all ischemic stroke subtypes.

Clinical practice data have demonstrated that tPA use outside a clinical trial setting also has a similar risk-benefit profile and thus maintains its efficacy. (Tanne D et al, 1999, Graham GD et al, 2003). It was found that hemorrhage and mortality significantly correlated with the number of protocol violations. Thus, strict adherence to the original NINDS protocol guidelines is absolutely necessary for safe and effective use of tPA for stroke.

Eligibility for IV tPA

Onset of stroke symptoms within 3 hours. (If symptoms were noticed upon awakening, then onset is assumed to be from time when patient went to sleep. If patient is discovered unconscious, then onset is assumed from the time when he was last seen normal) ;
No recent trauma or major surgery (2 weeks); GI or GU bleed (3 weeks); no serious head trauma, brain surgery, or stroke (3 months); (In these situations bleeding complications are more likely);
No rapidly improving symptoms (May be a transient ischemic attack (TIA);
No seizure at onset (May be postictal paralysis mimicking stroke);
Blood pressure < 185/110 without major interventions;
CT without intracerebral hemorrhage;
Normal glucose (50-400 mg/dL);
PT < 15: This can be drawn just before the tPA bolus if no recent heparin or warfarin, and if the measurement returns with too high a value, the tPA can be stopped;
Platelets #mt 1,00,000/mm³.

Practical Points

Tissue plasminogen activator (tPA) is administered intravenously in a dose of 0.9 mg per Kg body weight to be infused over one hour. The maximum dose should not exceed 90 mg. Ten percent of the calculated dose is given as a bolus over one minute and the remaining amount is infused over one hour.

It may be noted that antiplatelet use prior to the stroke is not a contraindication to tPA. The NINDS tPA trial and subsequent studies did not find a greater risk of hemorrhagic complications in those patients who were already taking antiplatelet agents. However, following tPA treatment, the protocol forbids any antithrombotic use, including antiplatelet agents and subcutaneous heparin for 24 hours, until a repeat head computed tomographic (CT) scan is performed to rule out intracranial hemorrhage.

Hypoglycemia, and to a lesser extent hyperglycemia, can cause focal neurologic symptoms and thus mimic stroke. A rapid measure of blood sugar by a glucometer should be obtained immediately. The NINDS trial excluded patients whose blood glucose was < 50 or #mt 400 mg/dL. Of note, even moderate hyperglycemia may negatively affect stroke outcome and add to the risk of ICH. Thus, elevated blood sugar should be aggressively treated in stroke patients.

Coagulopathy is a risk factor for hemorrhagic conversion with the use of a thrombolytic agent. Thus, patients with a PT #mt 15 cannot be given tPA. If the patient is known to be taking warfarin sodium or the patient's medications are not known, it is necessary to await the coagulation studies before proceeding with tPA use. However, if there is no history of anticoagulant use, underlying liver disease, or other coagulopathy, it is not necessary to wait for this laboratory result to proceed with tPA. If the coagulation laboratory studies return significantly abnormal after tPA has been started, the tPA infusion can be stopped and further diagnostic studies should be performed.

A complete blood count is useful to check whether the patient is severely anemic which may be a marker of an active or recent bleeding source, which would be a contraindication to the use of tPA. Moreover, thrombocytopenia is a contraindication to tPA use, and it should only be given if the patient's platelet levels are above 1,00,000/mm³.

The NINDS rtPA Stroke Study chose 185/110 as the blood pressure cutoff for safe use of tPA on the basis of pilot tPA studies.(Levy DE et al, 1994) Subsequent studies have confirmed a correlation between pretreatment blood pressure and risk of ICH. (Tanne D et al, 2002) Thus, before tPA use, conservative measures to lower blood pressure are advised. If conservative measures do not bring BP down to acceptable limits, thentPA should be abandoned. Avoid excessive lowering of the BP just to give tPA. Following tPA use, however, blood pressure should be aggressively treated with a goal of maintaining it at levels below 180/105. (Note that it is 5 mm Hg lower than the pretreatment cutoff.) However for a patient who has suffered ischemic stroke and is not a candidate for tPA, the American Heart Association recommends that the patient's blood pressure be allowed to autoregulate and that physicians should only reduce the blood pressure if it is greater than 220/120.(Adams HP et al, 2003). (See section on arterial hypertension below).

The NINDS rtPA protocol excludes patients with #oFrapidly improving symptoms#cF from being administered tPA. If a patient's deficits are caused by a TIA and the affected artery is already recanalized, using a thrombolytic agent would provide no benefit and would expose the patient to unnecessary risk of bleeding. However, most TIAs resolve within 15 minutes, and as soon as the artery has recanalized, you would expect the patient to rapidly improve. In addition, symptoms of patients with ischemic stroke commonly fluctuate during the hyperacute phase of their event, and many are still likely to end up with a significant infarct. Thus, if a patient is clearly improving, it is reasonable to watch that patient closely, but If the patient is not clearly moving toward full recovery, it is probably better to treat than to miss the time window because the patient is fluctuating.

The NINDS rtPA Stroke Study found that ICH was associated with increasing severity of the neurologic deficit and with hypodensity or edema seen on head CT (NINDS rt-PA Stroke Study Group, 1995). However, the investigators also reported that high-risk patients treated with tPA were still more likely to have a good outcome than those who received placebo, and there was no increase in the risk of severe disability or death, suggesting that despite a higher risk of hemorrhage overall, these patients should still be treated with tPA.

Some studies have suggested that age may be a risk factor for ICH (Hacke W et al, 2004). Nevertheless, there is no age cutoff for treatment, and patients should not be excluded on the basis of their age alone.

Sudden vomiting during tPA infusion may be a sign of rising intracranial pressure from an expanding hematoma. In this situation, the tPA infusion should be stopped and a non-contrast CT scan repeated immediately. If the repeat CT scan is negative, it is appropriate to restart and complete the tPA infusion. If ICH is present, the NINDS protocol recommends reversing the thrombolytic state with infusions of platelets and cryoprecipitate. PT/PTT, fibrinogen, CBC, and type and crossmatch should be checked immediately, and a neurosurgeon should be consulted for possible intervention, if indicated. Other signs of ICH include sudden severe headache, worsening neurologic symptoms (including a deteriorating level of arousal), and a sharp spike in blood pressure with accompanying bradycardia.

Following tPA, all patients should be monitored in an intensive care or stroke unit setting. The NINDS protocol recommends that blood pressure be checked every 15 minutes for the first 2 hours, every 30 minutes for the next 6 hours, and then every hour for the next 16 hours. Neuro checks are performed every hour for the first 24 hours in order to detect any possible deterioration.

Although tPA has clearly been shown to benefit stroke patients, a limited number of patients receive this treatment. Roughly 2% of acute stroke patients in the United States currently receive tPA (Katzan et al, 2004). The majority of patients with acute ischemic stroke are not being treated with tPA because they arrive at the emergency department after the 3-hour window. Even with the 3 hour window, the earlier one administers tPA, the greater the benefit (Marler et at, 2000). Thus, an aggressive campaign to educate the public about stroke symptoms and the importance of rapid evaluation is of paramount importance.

Approximately 50% of patients with acute ischemic stroke who arrive at the emergency department within 3 hours of symptom onset are good candidates for tPA (Katzan et al, 2004). Unfortunately, only about half of these patients are receiving the medicine. This is because emergency physicians are still not comfortable in administering tPA. A recent study found that emergency physicians rarely misdiagnose acute ischemic stroke before administering IV tPA, (4% misdiagnosis rate), and that patients with #oFstroke mimics#cF who received tPA fared well (Scott and Silbergleit, 2003).

IV tPA remains the best hope for an excellent outcome for patients with acute ischemic stroke, and timeliness and adherence to the protocol are the keys to safe and effective use of this medication.

Acute Antithrombotic Therapy: Heparin

There is still insufficient evidence to recommend the routine use of antithrombotic therapy such as IV heparin, low molecular weight heparin (LMWH), or heparinoids in the management of acute ischemic stroke. Antithrombotic therapy can be useful in a few conditions, however. These include arterial dissection and cortical venous thrombosis. In the latter condition it is recommended even in the prescence of hemorrhagic infarction. It may be useful in prevention of crescendo TIAs where antiplatelet agents have failed, and in prevention of cardioembolic events. In the setting of cardioembolic stroke however, it is recommended to first rule out hemorrhagic infarction by a non contrast cranial CT scan after 48 to 72 hours. Low dose heparin or LMWH can be routinely used in prevention of deep vein thrombosis.

General Measures

Supportive care is a significant component of acute stroke care. Discussed below are important general measures in management of acute ischemic or hemorrhagic stroke. In these measures lie the actual secrets of survival and reduced morbidity for the majority of stroke patients.

Airway and breathing

Most patients do not need endotracheal intubation or ventilatory assistance. However patients with massive brain edema, prominent bulbar dysfunction, or recurrent seizures will need intubation to protect the airway. This helps in preventing aspiration pneumonia. Patients with normal oxygen saturation do not need oxygen. Patients with hypoxia should be given supplemental oxygen (Ronning et al. 1999). Hypoventilation can result in increase in PCO2 and decrease in PO2 which can worsen neurologic status and increase intracranial pressure. Ventilatory assistance can be . started if hypoventilation occurs (Gujjar et al. 1998).

Fever

An elevated temperature can potentiate the effects of acute stroke, be it hemorrhagic or ischemic and is a poor prognostic sign. (Schwarz et al. 2000, Oliveira-Filho et al. 2001, Wang et al. 2000.) Fever can result from complications such as aspiration pneumonia or be a sign of an infectious cause of stroke such as endocarditis. Rarely it may have a central cause. Elevated leukocyte count, fever, an elevated fibrinogen, seen in acute phase reaction are predictors of secondary deterioration. Aggressive management of fever and attention to infection may improve outcome. (Audebert et al. 2004, Leira et al. 2004.)

Cardiac Complications Including Arrythmias

While on the one hand heart disease is an important cause of stroke, on the other hand cardiac disorders are potentially life threatening complications of cerebrovascular events. Myocardial ischemia, cardiac failure, pulmonary edema, and arrhythmias are potential complications of intracranial hemorrhage and major strokes. Cardiac monitoring is a necessary part of the initial observation of all patients with stroke, and abnormalities, if detected, should be treated as per the rules of advanced cardiac life support. (Myers et al. 1982.)

Arterial Hypertension

Elevated blood pressure is commonly seen during the first few hours of stroke. The high blood pressure can be a defense mechanism to maintain adequate perfusion to the brain. Cerebrovascular auto regulation is lost in the ischemic area and cerebral blood flow becomes dependent on blood pressure. Sudden lowering of the blood pressure may result in worsening of ischemia. Three recent prospective studies (Castillo et al. 2004, Oliveira-Filho et al. 2003, Vlcek et al. 2003) and one retrospective study (Semplicini et al. 2003) suggest that lowering BP in the first few hours of ischemic stroke results in worse neurologic outcome. The current recommendation for lowering blood pressure acutely if diastolic BP is greater than 120 or systolic BP is greater than 220 (Adams et al. 2003) is based on anecdotal evidence only and has no scientific basis or proven benefit. In acute ischemic stroke the blood pressure should generally not be lowered, except in certain situations which include hypertensive encephalopathy – a condition which is rare and erroneously over diagnosed, aortic dissection, acute renal failure, acute pulmonary edema, acute myocardial infarction and patients receiving thrombolytic therapy. The blood pressure in patients with intracranial hemorrhage, however, is usually treated more aggressively because severe hypertension can exacerbate intracranial bleeding. Here also, it should be lowered gradually (Mayberg et al. 1994).

Generally alleviating anxiety, pain, nausea and helping patient to empty bladder (without using a catheter if thrombolysis is planned, as it may cause a GU bleed in some patients and contraindicate thrombolysis) will by itself lower the blood pressure slightly. Oral antihypertensive medications are preferred and the aim is to cautiously lower the blood pressure by about 15% during the first 24 hours. Parenteral agents can be used in more urgent situations. Drugs which have rapid effect and short half-life arepreferred, so that if neurologic worsening occurs with a fall in BF their effect can be rapidly withdrawn. Potent long acting agents such as sublingual nifedipine should be avoided. Grossman et al. 1996). For treating patients undergoing thrombolytic therapy the choice of antihypertensive is intravenous nicardipine at 5mg/hr. This is given via constant infusion, is easily titratable, does not increase intracranial pressure, and does not require intraarterial BP monitoring. (Adam et al. 2003). Another choice is IV labetalol (10-20mg IV, repeated after 10-15 min. if necessary) or nitroprusside, depending upon the blood pressure values.

Fig. 1. The National Institutes of Health Stroke Scale

Hyperglycemia

Peristroke hyperglycemia may be a manifestation of underlying diabetes or a secondary stress reaction. It is associated with peri-infarct lactic acidosis, infarct extension and worse clinical outcomes. It may also reduce the efficacy of both IV and IA t-PA. (Parsons et al. 2002, Baird et al. 2003, Alvarez-Sabin J et al. 2003, Gray CS et al. 2004). Treatment of hyperglycemia is therefore recommended.

Seizures

Seizures complicate approximately 5% of strokes (Labovitz et al. 2001) and are most commonly seen in patients with subarachnoid hemorrhage or cortical infarctions secondary to embolism and cortical venous sinus thrombosis. Status epilepticus is uncommon. Frequent seizures can aggravate brain injury from stroke. Phenytoin/Fosphenytoin is the most commonly recommended anti-convulsant. Short acting IV Benzodiazepines can be given to abort active seizures. Prophylactic anti-convulsants in patients who have not had a seizure are usually not recommended.

Increased Intracranial Pressure

Severely elevated intracranial pressure may occur in multilobar hemispheric infarction, large hemispheric cerebral hematoma, large brain stem infarction or hematoma and large cerebellar infarction or hematoma. This can worsen brain ischemia by reducing cerebral blood flow Raised ICP is a result of brain edema or mass effect of the vascular lesion. It may be compounded by development of hydrocephalus.

Measures to control ICP include control of fever, agitation, nausea and vomiting, hypoxia and hypercarbia; restriction of fluids not more than 1.5 to 2 L/day; avoidance of potentially hypo-osmolar intravenous fluids such as 5% dextrose and elevating head of the bed to facilitate venous drainage. Osmotic diuretics such as Mannitol (in a 20% solution) 0.5 gm/kg may be given over 20-30 minutes, and 2.5 gm/kg every 6-8 hours to maintain serum osmolarity around 320 mOsm/L. Care should be taken to replace lost fluids due to diuresis and prevent a hyperosmolar state. Intravenous furosemide 20-40 mg may be effective. Corticosteroids are ineffective and are not recommended. Intubation and hyperventilation to lower PC02 to about 30mm Hg is an effective measure to reduce ICF but its effects lasts for about 24 hours only. It should therefore be used at a time when the ICP is peaking, usually on day 3 or 4 after the stroke. Large doses of barbiturates to induce a hypometabolic coma have been used to lower ICP but the usefulness of this technique has not been fully established. (Schwab et al. 1997).

Drainage of the CSF via an intraventricular catheter in patients with hydrocephalus can lower the ICP dramatically. Continuous CSF drainage can be done, especially in patients with subarachnoid hemorrhage. Repeated lumbar punctures can be helpful in patients who do not have an intracranial mass, for example, severe subarachnoid hemorrhage without a focal hematoma.

Large Hematoma or infarction causing mass effects

Large infarctions or hematomas of the cerebellar hemisphere are especially amenable to surgical evacuation. This can be a life saving measure by preventing secondary compression of the brain stem or acute hydrocephalus from developing. These patients need to be monitored closely because decompensation can occur rapidly necessitating immediate surgery. (Wijdicks et al. 2000, Chen et al. 1992, Matthew et al. 1995). In the case of thalamic or basal ganglia hematomas surgical evacuation may save a patient's life but commonly leave the patient in a vegetative state (Femandes et al. 2000). Large lobar hematomas in the frontal, temporal, and parietal lobes which are not responding to medical management can be treated operatively especially if they are located close to the surface. In patients with large hemispheric infarctions and massive brain edema with mass effect, decompressive craniectomy with or without resection of a section of necrotic brain can be a life saving measure for critically ill patients. Nevertheless the usefulness of this procedure has not been established because survival can be associated with severe neurologic residual deficit. However some patients with non dominant hemisphere infarctions can achieve good outcomes.

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