- Email: [email protected]
Acute Stroke — Current Management-Strategies
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ACUTE STROKE - CURRENT MANAGEMENT-STRATEGIES Pushpendra N. Renjen From the Department of Neurology, Apollo Neuro Sciences Centre, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 044, India. Correspondence to: Dr. Pushpendra N. Renjen, Senior Consultant Neurology, Apollo Neuro Sciences Centre, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 044, India. E-mail: [email protected] Stroke is the third common cause of death after cancer and heart disease, with rapid urbanization and industrialization, stroke will take an epidemic proportion, as predicts WHO by 2020. Recent advances in the management of stroke, with more stroke units have decreased the mortality and morbidity of stroke. Thrombolysis done within the first 3 hours improves the outcome in 30% patients. Prevention remains the corner stone, the modifiable risk factor have to be treated and prevented. Key words: Ischemic, Cerebral blood flow, Thrombolysis, Blood pressure.
STROKE is defined as rapidly developing (usually over minutes) clinical symptoms or signs of focal and/or at times global disturbance of cerebral function, lasting for more than 24 hours or leading to death with no apparent cause other than that of vascular origin [1]. It is the third leading cause of mortality and disability in developed countries after cancer and heart diseases [2]. It is the largest single cause of severe disability in people living at home. Its incidence averages 179 per 100,000 per year worldwide with a prevalence of 500-600 per 100,000. Various Indian epidemiological studies have reported its prevalence to be as low as 45 to as high as 800 per 100,000 population. Stroke contributes 2% of all hospital admissions, 4.5% of all medical admissions and 20% of all neurological admissions in India. The high incidence of stroke in younger population is peculiar in India. Various series report the incidence of stroke in young adults from 18.8 to 32% of all stroke cases [3]. After an acute stroke, 20-30% of patients die in first few days. Amongst the survivors 25% are rendered permanently disabled. Early recurrence adds to neurological deficit and lengthens hospital stay while late recurrence affects 4-14% per year and five year survival averages only 56% for men and 44% for women.
edema). This stage is reversible. Further fall of CBF to below 10 mL/100g/ minute causes cellular failure; aerobic mitochondrial metabolism fails, resulting in anerobic metabolism and lactic acidosis. At this stage Ca++ also enters the cells worsening the situation, resulting in cellular death. CBF below 10 mL/100 g/minute is irreversible. In any infarction there is a central core where the CBF is below 10 mL/100 g/ minute, which cannot be salvaged. A large area surrounds this area with CBFR between 10-50 mL/100 g/ minute. This is responsible for the clinical symptomatology because of electrical failure (because it is non-functional) but is salvageable, if adequate timely intervention is done to improve perfusion neuroprotection. This area is called “Ischemic Penumbra” and can be rescued [4-5] (Table 1). The therapeutic time window If an intervention is to be done it should be done within the therapeutic time window, before the ischemic penumbra passes on to irreversible stage of cellular membrane failure (homeostatic failure). In experimental rats this therapeutic window is only 60-90 minutes, and 2-3 hours in some other experiments. This means that all interventions should be done within 3 hours and the earlier it is done the better are the results. However, since it is difficult to get patients soon after a stroke, some studies include patients upto 6 hours of stroke. About 50% penumbra may still survive up to 72 hours.
PATHOPHYSIOLOGY OF STROKE Identification of salvageable ischemic penumbra Normal cerebral blood flow (CBF) is >50 mL/100g/ minute. Ischemic stroke occurs due to occlusion of a cerebral artery or less often due to reduction in perfusion distal to a severely stenosed artery. When the CBF falls to critical level of 20 mL/100g/minute there is loss of neuronal electrical function which is due to membrane Na ± K ± ATPase failure, and membrane depolarization, resulting in efflux of K+ , influx of Na+ along with consequent swelling of cells (cytotoxic
Cellular cascade following brain ischemia Cellular ischemia leads to cascade changes, which are deleterious to the tissues. Understanding of this cascade can help us to provide therapeutic intervention at various levels in the cascade [4-5]. 1. The first event is membrane depolarization resulting in 44
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GENERAL MEASURES IN PREVENTION OF MEDICAL COMPLICATION IN STROKE
membrane failure which in turn results in efflux of K+, influx of Na+ with water, finally influx of Ca++ causing proteolysis, lipolysis and cell death ( associated with free radical formation and disruption of cyto-skeleton).
Pulmonary-function and airway protection Like in the emergency room, adequate blood oxygenation with normal respiratory function is required for stroke management, although there is no convincing prospective clinical evidence that oxygen supply at low rates is useful in human brain infarction, adequate oxygenation and hyperventilation are without effect on a structurally damaged ischemic region, but they may be important for the preservation of metabolic turnover in the marginal zone of the insult, the so-called penumbra [5,6] (Table 2).
2. Ischemic depolarization results in uncontrolled release of excitatory neuro-transmitter, glutamate, which is neurotoxic. Glutamate activates NMDA, (causing further Na+ and Ca++ influx and K+ efflux and further cellular damage) and AMPA receptors ( with similar effect). Glutamate stimulates metabotropic receptors resulting in activation of phospholipases with release of Ca++ and free fatty acids, which are toxic. A lot of substances such as prostaglandin, thromboxanes and leukotrienes are also released which are toxic to the cell membrane causing its lysis and generation of free radicals.
A threatened airway may be found in patients with severe pneumonia, heart failure, extensive vertebrobasilar or hemispheric infarction, with large intracranial hemorrhages or with patients with sustained seizure activity following hemispheric stroke. Overt pulmonary dysfunction is occasionally present in the form of slightly exacerbated chronic obstructive airway disease. Some patients develop early AV shunts and require oxygen or even intubation and ventilation. Aterial blood gas analysis (ABG) or an expiratory pCO2 and transcutaneous O2 assessment should be performed early in selected patients with either severe stroke or impaired pulmonary function. Ventilation may be particularly compromised during sleep.
3. Generation of free radical by various mechanisms as explained above is also toxic to the cells and causes ischemic neurotoxicity. 4. An inflammatory response to ischemic neuronal damage leads to the release of interleukins, leucocyte adhesion, production of arachidonic acid and toxic free radical formation. 5. Reperfusion, either by endogenous thrombolysis, thrombus migration or therapeutic intervention may aggravate ischemic damage by production of toxic free radicals from reperfusion tissue and release of cytokines with resultant leucocyte adhesion.
Cardiac Care and Blood Pressure Management
6. Apoptosis or “programmed cell death” also occurs in ischemic neurons. This is a slow process due to controlled cascade of intracellular events. It is not known as to what triggers this.
Cardiac arrhythmias secondary to stroke are not unusual. Significant alterations in the ST segments and the T waves on the EKG may appear in the acute phase mimicking myocardial ischemia and cardiac enzymes may be elevated after stroke. Every stroke patient should have an initial EKG. If this is normal, usually no continuous EKG monitoring is required. However, patients with major stroke syndromes and some hemodynamic instability should be continuously monitored in an ICU. Not all cardiac phenomena after cerebral ischemia should be regarded as secondary. There is a coincidence of myocardial infarction, sometimes not particularly clinically
TABLE 1. Critical cerebral blood flow levels and their effects. CBF
Effect
50 mL/100 g/min
Normal
Normal function
20 mL/100 g/min
Electrical failure
Loss of neuronal function Failure of Na ± K ± ATPase
Cytotoxic
Na+, K+ efflux
Edema
Reversible
Cellular failure
Mitochondrial failure, Lactic acidosis
10 mL/100 g/min
Result
TABLE 2. Guidelines for treating stroke patients. 1. Patients should be treated in a stroke unit 2. Neurological status and vital functions should be monitored regularly
Release of excitatory amino-acid
3. Secure airways and provide adequate oxygenation 4. Do not treat hypertension in the first phase after stroke if there are no extremely high values or internal indication
Glutamate, Ca+ influx Cell death 10 to 20 mL/ 100 g/min
Ichemic penumbra
Irreversible
5. Monitor glucose and body temperature and correct them, if elevated
Can be rescued if timely treated
6. Close monitoring and correction of electrolyte disturbances is advised
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impressive; with cerebral ischemia use of digitalis is only reasonable when there are obvious signs of myocardial insufficiency.
Non of the recommendations concerning general treatment has been verified in placebo-controlled, randomised, blinded studies. However, the proven efficacy of stroke units to some extent may be caused by adherence to guidelines for general treatment, which may be used as an indirect proof of efficacy of general treatment procedures.
Blood Pressure Management In acute stroke ‘cerebral autoregulation’ is lost and blood flow in the infarcted areas is solely dependent on mean arterial BP. In the presence of severe hypertension (e.g., blood pressure over 220/120 mmHg) parenteral therapy with titratable agents such as IV labetolol, nitroprusside or enalapril, which reduce blood pressure smoothly are recommended. Calcium channel blockers are best avoided because they produce severe drop in blood pressure in some patients. On the other hand, raised blood pressure levels in hypertensive and non-hypertensive stroke-subjects often fall unpredictably within 24 hours to few days; which may hamper perfusion in zone of ischemic penumbra leading to irreversible injury. Therefore, any significant hypotensive episode should be promptly treated to prevent extension of cerebral infarction [6,7].
SPECIFIC TREATMENT Thrombolytic therapy. With rtPA (0.9 mg/kg body weight) given within 3 hours after stroke onset to patients with acute ischemic stroke significantly improves outcome after stroke (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. NINDs, 1995) [14,15]. This treatment is not yet approved in Europe, while it is in North America. There is evidence that thrombolysis may also work upto 6 hours after stroke onset in carefully identified patients. The result of ATLANTIS, a 3-5 hours randomized rtPA trial did not show any effects on outcome or mortality. This therapy is not undisputed. In Europe, there is still some doubt about its risk benefit ratio, which prevents some centers from actively promoting it. Caution is advised before giving intravenous rtPA to persons with severe stroke (NIH Stroke Scale >22), or if the CT demonstrates extended early changes of a major infarction, such as sulcal effacement, mass effect and edema. In centers where thrombolytic therapy is offered, it should only be given if a physician who has expertise in the diagnosis of stroke establishes the diagnosis, and physicians who have expertise in reading this imaging study assess a CT of the brain. Because the use of thrombolytic drugs carries the real risk of major bleeding, the risks and potential benefits of rtPA should be discussed whenever possible with the patient and family before treatment is initiated. A recent meta-analysis of all randomized rtPA trials demonstrates an increase in independent reviewers, thrombolysis in acute ischemic stroke seems to be increasingly robust within 3 and possibly 6 hours of stroke. However, the Cochrane reviewers still consider the number of patients randomised to be too small so that there is little evidence on which subgroups of stroke might particularly benefit or be harmed, and hence not enough evidence to draw final conclusions about the effect of thrombolytic drugs in acute stroke. Intravenous administration of rtPA more than 3 hours after stroke should only be given in institutional protocol as experimental therapy. Intra-arterial thrombolytic therapy of occlusion of the proximal part of the middle cerebral artery, using pro-uro-kinase, has been shown to be significantly associated with better outcome in a recently published randomized trial [12]. This treatment requires superselective angiography and is only available in selected centers. The treatment is safe and efficacious in a 6 hours time window.
Body Temperature Fever negatively influences neurological outcome after stroke. Infection is a risk factor for stroke, and many patients develop an infection after stroke. Antipyretics such as paracetamol and the early use of antibiotics in cases of apparent bacterial infection such as urinary tract infection or aspiration pneumonia are usually recommended. Although there are no prospective data,one may consider lowering body temperature as soon as it reaches 37.5º C [8,9]. Serum Glucose Experimental models suggest that persistent hyperglycemia worsens ischemic cerebral injury. Several clinical trials have shown a correlation between increased morbidity and mortality and high serum glucose levels, almost like a dose-response relationship. Animal models suggest that hyperglycemia at onset of ischemic cerebral injury carries grave prognosis. Thus, careful monitoring of serum glucose levels, for hypo and hyperglycemia, and timely therapeutic intervention will prevent extension of injury. Furthermore, elevated glucose concentration may increase production of lactic acid in ischemic tissue. This may be corrected by insulin therapy. Fluid and Electrolyte Management Stroke patients should have a balanced fluid and electrolyte status to avoid plasma volume contraction, raised hematocrit and impairment of rheologic properties of the blood (‘sludging’). In the presence of raised intracerebral pressure, a slightly negative fluid balance ( about 300-500 ml negative balance daily) is usually recommended. The electrolytes should be monitored daily and substituted accordingly. Apollo Medicine, Vol.1, September 2004
RECOMMENDATIONS FOR CENTERS OFFERING THROMBOLYSIS 1. Intravenous rt PA (0.9mg/kg: maximum 90 mg) with 10% 46
Personal Practice
2.
3.
4.
5.
6.
7.
reduction in stroke recurrence rates, this was almost always counterbalanced by an increased number of hemorrhagic complications. In the past 10 years, no randomised studies have been performed to test the effects of early full anticoagulation with conventional heparin following acute ischemic stroke, which is still used frequently in many centers. In addition, many investigator believe that heparin is not and never will be a standard therapy for all stroke subtypes. However, they believe that high-risk patients ( such as patients with stroke associated with atrial fibrillation) should be studied separately. Such a study is not available right now, and therefore, the remaining indications for the use of acute heparin after ischemic stroke are not evidence based. Table 3 gives some indications as to when full-dose intravenous heparin may currently still be proposed.
of the dose given as a bolus followed by an infusion lasting 60 minutes is the recommended treatment within 3 hours of onset of ischemic stroke. The benefit from the use of intravenous rtPA for acute ischemic stroke beyond 3 hours onset of the symptoms is smaller, but present in selected patients. Intravenous rtPA is not recommended when the time of onset of stroke cannot be ascertained reliably. This includes persons whose strokes cannot be ascertained reliably this includes person whose strokes are recognised upon awakening. Intravenous administration of streptokinase, outside the setting of a clinical investigation, is dangerous and not indicated for the management of persons with ischemic stroke. Data on efficacy or safety of any other intravenously administered thrombolytic drugs are not available to provide a recommendation. Intra-arterial treatment of acute middle cerebral artery occlusion in a 6 hours time window using pro-urokinase results in a significantly improved outcome. Acute basilar occlusion may be treated with intra-arterial therapy in selected centers.
Usually, it is recommended to elevate the partial thromboplastin time upto twice the individual baseline. Heparin should only be given as long as it takes to decide on the appropriate secondary prevention. Contraindications for the treatment with haparin include large infarcts ( e.g., more than 50% of MCA territory), uncontrollable arterial hypertension and advanced microvascular changes in the brain. Hemodilution [10,11]
Defibrinogenating Enzymes
Isovolemic hemodilution that lowers the hematocrit by 15% or more results in reduction in blood viscosity and improvements CBF [15,16]. Several large clinical trials of isovolemic hemodilution were unable to demonstrate a decline in mortality or disability with treatment. Hypervolemic hemodilution has been examined in small randomised trials with conflicting results. The clinical benefit of hemodilution therapy has not been established, and the possibility of excess brain edema has not been excluded.
Ancrod, a defibrinogenating enzyme has been shown to improve outcome after acute ischemic stroke if given within 3 hours after stroke onset and over 5 days. Recently, a European trial testing ancrod treatment in a 6 hours time window has been terminated prematurely. Platelet Inhibitors The results of two very large randomised, non-blinded intervention studies indicate that aspirin given within 48 hours after stroke ( ICT, CAST) seems to reduce mortality and rate of recurrent stroke minimally, but statistically significantly. Whether the mild positive effect of early aspirin is due to an effect on the infarct itself or due to prevention of recurrent infarction is not yet clear. It may be discussed that the NTN anti-inflammatory effect of aspirin may also influence the overall result [13].
Neuroprotection Not a single neuroprotective agent has been shown to
TABLE 3. Remaining indications for heparin treatment after stroke. • Stroke due to cardiac emboli with high risk of reembolisation (artificial valves, atrial fibrillation, MI with mural thrombi, left atrial thrombosis.
Early Anticoagulation Has been used frequently in the treatment after acute ischemic stroke. Unfortunately, none of the trials that have been performed in the past years has supported the idea that early heparin may influence outcome after ischemic stroke or at least may reduce the number of recurrent strokes [14]. Several studies that used intravenous heparinoids, subcutaneous low-molecular-weight heparin or subcutaneous heparin failed to show an overall benefit of the treatment. While there was some kind of improvement in the outcome or
• Coagulopathies such as protein C and S deficiency, APC resistance. • Symptomatic dissection of extracranial arteries. • Symptomic extra-and intracranial stenoses. • Symptoms of internal carotid stenosis prior to operation. • Crescendo TIAs or stroke in progression. • Sinus venous thrombosis.
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Recommendations
influence the outcome after stroke. Currently, there is no recommendation to treat patients with neuroprotective drugs after ischemic stroke.
1. Administration of heparin or low-molecular - weight heparin in bedridden patients after stroke is recommended to reduce the number of DVT and pulmonary embolism. However, there is a risk of additional intracranial bleeding. 2. Infections after stroke should be treated with appropriate antibiotics. Aspiration pneumonia may be prevented by nasogastric feeding. 3. Early mobilisation is helpful to prevent numerous complications after stroke including aspiration pneumonia, DVT and decubital ulcers. 4. Administration of anticonvulsants to prevent recurrent seizure is strongly recommended. 5. Prophylactic administration of anticonvulsants to patients with recent stroke who have not had seizures is not recommended.
Recommendations 1. There is no recommendation for general use of heparin, low-molecular heparin or heparinoids after ischemic stroke. 2. Full-dose heparin may be used when there are selected indications such as atrial fibrillation, other cardiac sources with high risk of re-embolism, arterial dissection or highgrade arterial stenosis. 3. Aspirin (100-300 mg per day) may be given after stroke to an unselected population, even without CT scan. 4. Hemodilutin therapy is not presently recommended for the management of patients with acute ischemic stroke. 5. Currently, there is no recommendation to treat patients with neuroprotective substance of the ischemic stroke.
Reduction of Increased Intracranial Pressure and Cerebral Edema The head should be elevated by 30 degree in case of raised intracranial pressure ( ICP). Intubation and hyperventilation to keep partial pressure of CO2 to 25-30 mmHg would be helpful in cases associated with increasing drowsiness. In hypertensive crisis (Blood pressure >240/130 mmHg), sodium nitroprusside is advocated but parenteral use of betablockers with IV atropine and frusemide are preferred. The blood pressure should be carefully monitored and never precipitately lowered. In the first week of massive cerebral infarction with evidence of fluid retention, dehydration with hyperosmolar solution (e.g., IV mannitol) is often tried to reduce vasogenic brain edema, but its effect is short-lasting and rebound cerebral edema may prove harmful. Furthermore, in subjects with incipient left ventricular failure, such agents can precipitate pulmonary edema. High doses of corticosteroids (dexamethasone 24-40 mg/day in divided doses parenterally) can reduce vasogenic cerebral edema, but their routine use in treatment of ischemic strokes is doubtful [11].
Prevention and treatment of complications. Acute stroke predisposes to medical complications such as pneumonia, urinary tract infections, malnutrition and volume depletion. Patients may also suffer from DVT and pulmonary embolism. Early supportive care and monitoring of physiological parameters may prevent such complications. This is best done in a dedicated stroke unit with experienced staff and early mobilisation. Immobility may lead to infections, contractions and decubital ulcers. Pulmonary Embolism and DVT Prevention of acute pulmonary embolism is of major importance in the care of every patient with stroke. Pulmonary embolism is the cause of death in upto 25% of patients dying following ischemic cerebral infarction, even in patients who otherwise would have had an excellent recovery from the stroke. The risk of DVT and pulmonary embolism can be reduced by early mobilisation and by the use of subcutaneous heparin or low-molecular weight heparin. However, this effect seems to be counter-balanced by an increase in hemorrhagic complications. Prophylaxis with subcutaneous low-dose heparin, 7,500-10,000 IU every 12 hours has been recommended for stroke patients. Pneumatic compression stockings are recommended for patients restricted to their bed, as they can further decrease the risk of DVT. Tachypnea and pain are sensitive sign of pulmonary embolism (and of pneumonia). Since chest pain and dyspnea will occur in 7080% of those patients with documented pulmonary embolism, nurses and physicians should be attentive to these signs. Examination of lower extremities should be performed daily to detect signs of DVT. Physical therapy and support stockings are suggestive as alternatives. Apollo Medicine, Vol.1, September 2004
Summary
48
•
Safe and effective treatment is now available for patients with acute ischemic strokes. Intravenous thrombolysis with rtPA is safe and improves outcome if treatment is initiated within three hours after the onset of symptoms.
•
Inttra-arterial revascularisation may provide more complete restitution of flow in the middle cerebral artery than intravenous thrombolytic therapy.
•
Intra-arterial therapy may also improve the clinical outcome if it can be undertaken within the first six hours after the onset of symptoms.
•
Antithrombotic drugs lessen the likelihood of deep-vein
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•
thrombosis and aspirin offers a moderate benefit in the prevention of recurrent stroke.
in acute stroke: Relation to stroke severity, infarct size, mortality and outcome. Lancet 1996; 347: 422-425.
Advances in the understanding of the rehabilitation process and its implementation will continue to produce improvements in both short-term and long-term quality of life among patients who survive a stroke.
9. Schwab S, Spranger M, Aschoff A, et al. Brain temperature monitoring and modulation in patients with severe MCA infarction. Neurology 1997; 48: 762-767. 10. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European cooperative acute stroke study. JAMA 1995; 274: 1017-1025.
REFERENCES 1. Hatano S. Experience from a multicentre stroke register. Bull WHO 1976; 54 : 541-553.
11. Dalal PM. Thrombolytic therapy in ischaemic stroke. Neurol India 1997; 45: 127-131.
2. Warlow CP. Epidemiology of stroke. Lancet 1998; 352: ( Suppl. III), 1-6.
12. del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Insvestigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 1998; 29: 4-11.
3. Dalal PM. Strokes in young and elderly: risk factors and strategies for stroke prevention. JAPI 1997; 45: 125-131. Also in Indian J Med Res 1997; 106: 325-332. 4. Dalal PM. Ischaemic strokes : early intensive treatment. In ‘Medicine update’ ( APICON - 98) Vol.8 Supplement Das AK (ed.) All India Press, Pondicherry. 1998; 82-92.
13. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischaemic stroke. Stroke 2000; 31: 1240. 14. International stroke trial collaborative group (IST). A randomized trial of aspirin, heparin, both or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569-1581.
5. Dalal PM. Neurological complications of cardiac interventions. In: Reviews in Neurology 2000. 6. Bath F; Bath P. Blood pressure in acute stroke collaboration. Cerebrovasc Dis 1997; 7: 205-213.
15. Scandinavian stroke study group. Multicentre trial of hemodilution in acute ischaemic stroke-1. Result of sub group analyses. Stroke 1988; 19: 464-471.
7. Boiser JC, Lichtman J, Cerese J, et al. Treatment of hypertension in acute ischaemic stroke: the university health consortium stroke benchmarking project. Stroke 1998; 29: 305.
16. Italian acute stroke group. Hemodilution in acute stroke. Lancet 1988; 1: 318.
8. Reith J, Jorgensen S, Pedersen PM, et al: Body temperature
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ACUTE STROKE - CURRENT MANAGEMENT-STRATEGIES Pushpendra N. Renjen From the Department of Neurology, Apollo Neuro Sciences Centre, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 044, India. Correspondence to: Dr. Pushpendra N. Renjen, Senior Consultant Neurology, Apollo Neuro Sciences Centre, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 044, India. E-mail: [email protected] Stroke is the third common cause of death after cancer and heart disease, with rapid urbanization and industrialization, stroke will take an epidemic proportion, as predicts WHO by 2020. Recent advances in the management of stroke, with more stroke units have decreased the mortality and morbidity of stroke. Thrombolysis done within the first 3 hours improves the outcome in 30% patients. Prevention remains the corner stone, the modifiable risk factor have to be treated and prevented. Key words: Ischemic, Cerebral blood flow, Thrombolysis, Blood pressure.
STROKE is defined as rapidly developing (usually over minutes) clinical symptoms or signs of focal and/or at times global disturbance of cerebral function, lasting for more than 24 hours or leading to death with no apparent cause other than that of vascular origin [1]. It is the third leading cause of mortality and disability in developed countries after cancer and heart diseases [2]. It is the largest single cause of severe disability in people living at home. Its incidence averages 179 per 100,000 per year worldwide with a prevalence of 500-600 per 100,000. Various Indian epidemiological studies have reported its prevalence to be as low as 45 to as high as 800 per 100,000 population. Stroke contributes 2% of all hospital admissions, 4.5% of all medical admissions and 20% of all neurological admissions in India. The high incidence of stroke in younger population is peculiar in India. Various series report the incidence of stroke in young adults from 18.8 to 32% of all stroke cases [3]. After an acute stroke, 20-30% of patients die in first few days. Amongst the survivors 25% are rendered permanently disabled. Early recurrence adds to neurological deficit and lengthens hospital stay while late recurrence affects 4-14% per year and five year survival averages only 56% for men and 44% for women.
edema). This stage is reversible. Further fall of CBF to below 10 mL/100g/ minute causes cellular failure; aerobic mitochondrial metabolism fails, resulting in anerobic metabolism and lactic acidosis. At this stage Ca++ also enters the cells worsening the situation, resulting in cellular death. CBF below 10 mL/100 g/minute is irreversible. In any infarction there is a central core where the CBF is below 10 mL/100 g/ minute, which cannot be salvaged. A large area surrounds this area with CBFR between 10-50 mL/100 g/ minute. This is responsible for the clinical symptomatology because of electrical failure (because it is non-functional) but is salvageable, if adequate timely intervention is done to improve perfusion neuroprotection. This area is called “Ischemic Penumbra” and can be rescued [4-5] (Table 1). The therapeutic time window If an intervention is to be done it should be done within the therapeutic time window, before the ischemic penumbra passes on to irreversible stage of cellular membrane failure (homeostatic failure). In experimental rats this therapeutic window is only 60-90 minutes, and 2-3 hours in some other experiments. This means that all interventions should be done within 3 hours and the earlier it is done the better are the results. However, since it is difficult to get patients soon after a stroke, some studies include patients upto 6 hours of stroke. About 50% penumbra may still survive up to 72 hours.
PATHOPHYSIOLOGY OF STROKE Identification of salvageable ischemic penumbra Normal cerebral blood flow (CBF) is >50 mL/100g/ minute. Ischemic stroke occurs due to occlusion of a cerebral artery or less often due to reduction in perfusion distal to a severely stenosed artery. When the CBF falls to critical level of 20 mL/100g/minute there is loss of neuronal electrical function which is due to membrane Na ± K ± ATPase failure, and membrane depolarization, resulting in efflux of K+ , influx of Na+ along with consequent swelling of cells (cytotoxic
Cellular cascade following brain ischemia Cellular ischemia leads to cascade changes, which are deleterious to the tissues. Understanding of this cascade can help us to provide therapeutic intervention at various levels in the cascade [4-5]. 1. The first event is membrane depolarization resulting in 44
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GENERAL MEASURES IN PREVENTION OF MEDICAL COMPLICATION IN STROKE
membrane failure which in turn results in efflux of K+, influx of Na+ with water, finally influx of Ca++ causing proteolysis, lipolysis and cell death ( associated with free radical formation and disruption of cyto-skeleton).
Pulmonary-function and airway protection Like in the emergency room, adequate blood oxygenation with normal respiratory function is required for stroke management, although there is no convincing prospective clinical evidence that oxygen supply at low rates is useful in human brain infarction, adequate oxygenation and hyperventilation are without effect on a structurally damaged ischemic region, but they may be important for the preservation of metabolic turnover in the marginal zone of the insult, the so-called penumbra [5,6] (Table 2).
2. Ischemic depolarization results in uncontrolled release of excitatory neuro-transmitter, glutamate, which is neurotoxic. Glutamate activates NMDA, (causing further Na+ and Ca++ influx and K+ efflux and further cellular damage) and AMPA receptors ( with similar effect). Glutamate stimulates metabotropic receptors resulting in activation of phospholipases with release of Ca++ and free fatty acids, which are toxic. A lot of substances such as prostaglandin, thromboxanes and leukotrienes are also released which are toxic to the cell membrane causing its lysis and generation of free radicals.
A threatened airway may be found in patients with severe pneumonia, heart failure, extensive vertebrobasilar or hemispheric infarction, with large intracranial hemorrhages or with patients with sustained seizure activity following hemispheric stroke. Overt pulmonary dysfunction is occasionally present in the form of slightly exacerbated chronic obstructive airway disease. Some patients develop early AV shunts and require oxygen or even intubation and ventilation. Aterial blood gas analysis (ABG) or an expiratory pCO2 and transcutaneous O2 assessment should be performed early in selected patients with either severe stroke or impaired pulmonary function. Ventilation may be particularly compromised during sleep.
3. Generation of free radical by various mechanisms as explained above is also toxic to the cells and causes ischemic neurotoxicity. 4. An inflammatory response to ischemic neuronal damage leads to the release of interleukins, leucocyte adhesion, production of arachidonic acid and toxic free radical formation. 5. Reperfusion, either by endogenous thrombolysis, thrombus migration or therapeutic intervention may aggravate ischemic damage by production of toxic free radicals from reperfusion tissue and release of cytokines with resultant leucocyte adhesion.
Cardiac Care and Blood Pressure Management
6. Apoptosis or “programmed cell death” also occurs in ischemic neurons. This is a slow process due to controlled cascade of intracellular events. It is not known as to what triggers this.
Cardiac arrhythmias secondary to stroke are not unusual. Significant alterations in the ST segments and the T waves on the EKG may appear in the acute phase mimicking myocardial ischemia and cardiac enzymes may be elevated after stroke. Every stroke patient should have an initial EKG. If this is normal, usually no continuous EKG monitoring is required. However, patients with major stroke syndromes and some hemodynamic instability should be continuously monitored in an ICU. Not all cardiac phenomena after cerebral ischemia should be regarded as secondary. There is a coincidence of myocardial infarction, sometimes not particularly clinically
TABLE 1. Critical cerebral blood flow levels and their effects. CBF
Effect
50 mL/100 g/min
Normal
Normal function
20 mL/100 g/min
Electrical failure
Loss of neuronal function Failure of Na ± K ± ATPase
Cytotoxic
Na+, K+ efflux
Edema
Reversible
Cellular failure
Mitochondrial failure, Lactic acidosis
10 mL/100 g/min
Result
TABLE 2. Guidelines for treating stroke patients. 1. Patients should be treated in a stroke unit 2. Neurological status and vital functions should be monitored regularly
Release of excitatory amino-acid
3. Secure airways and provide adequate oxygenation 4. Do not treat hypertension in the first phase after stroke if there are no extremely high values or internal indication
Glutamate, Ca+ influx Cell death 10 to 20 mL/ 100 g/min
Ichemic penumbra
Irreversible
5. Monitor glucose and body temperature and correct them, if elevated
Can be rescued if timely treated
6. Close monitoring and correction of electrolyte disturbances is advised
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Personal Practice
impressive; with cerebral ischemia use of digitalis is only reasonable when there are obvious signs of myocardial insufficiency.
Non of the recommendations concerning general treatment has been verified in placebo-controlled, randomised, blinded studies. However, the proven efficacy of stroke units to some extent may be caused by adherence to guidelines for general treatment, which may be used as an indirect proof of efficacy of general treatment procedures.
Blood Pressure Management In acute stroke ‘cerebral autoregulation’ is lost and blood flow in the infarcted areas is solely dependent on mean arterial BP. In the presence of severe hypertension (e.g., blood pressure over 220/120 mmHg) parenteral therapy with titratable agents such as IV labetolol, nitroprusside or enalapril, which reduce blood pressure smoothly are recommended. Calcium channel blockers are best avoided because they produce severe drop in blood pressure in some patients. On the other hand, raised blood pressure levels in hypertensive and non-hypertensive stroke-subjects often fall unpredictably within 24 hours to few days; which may hamper perfusion in zone of ischemic penumbra leading to irreversible injury. Therefore, any significant hypotensive episode should be promptly treated to prevent extension of cerebral infarction [6,7].
SPECIFIC TREATMENT Thrombolytic therapy. With rtPA (0.9 mg/kg body weight) given within 3 hours after stroke onset to patients with acute ischemic stroke significantly improves outcome after stroke (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. NINDs, 1995) [14,15]. This treatment is not yet approved in Europe, while it is in North America. There is evidence that thrombolysis may also work upto 6 hours after stroke onset in carefully identified patients. The result of ATLANTIS, a 3-5 hours randomized rtPA trial did not show any effects on outcome or mortality. This therapy is not undisputed. In Europe, there is still some doubt about its risk benefit ratio, which prevents some centers from actively promoting it. Caution is advised before giving intravenous rtPA to persons with severe stroke (NIH Stroke Scale >22), or if the CT demonstrates extended early changes of a major infarction, such as sulcal effacement, mass effect and edema. In centers where thrombolytic therapy is offered, it should only be given if a physician who has expertise in the diagnosis of stroke establishes the diagnosis, and physicians who have expertise in reading this imaging study assess a CT of the brain. Because the use of thrombolytic drugs carries the real risk of major bleeding, the risks and potential benefits of rtPA should be discussed whenever possible with the patient and family before treatment is initiated. A recent meta-analysis of all randomized rtPA trials demonstrates an increase in independent reviewers, thrombolysis in acute ischemic stroke seems to be increasingly robust within 3 and possibly 6 hours of stroke. However, the Cochrane reviewers still consider the number of patients randomised to be too small so that there is little evidence on which subgroups of stroke might particularly benefit or be harmed, and hence not enough evidence to draw final conclusions about the effect of thrombolytic drugs in acute stroke. Intravenous administration of rtPA more than 3 hours after stroke should only be given in institutional protocol as experimental therapy. Intra-arterial thrombolytic therapy of occlusion of the proximal part of the middle cerebral artery, using pro-uro-kinase, has been shown to be significantly associated with better outcome in a recently published randomized trial [12]. This treatment requires superselective angiography and is only available in selected centers. The treatment is safe and efficacious in a 6 hours time window.
Body Temperature Fever negatively influences neurological outcome after stroke. Infection is a risk factor for stroke, and many patients develop an infection after stroke. Antipyretics such as paracetamol and the early use of antibiotics in cases of apparent bacterial infection such as urinary tract infection or aspiration pneumonia are usually recommended. Although there are no prospective data,one may consider lowering body temperature as soon as it reaches 37.5º C [8,9]. Serum Glucose Experimental models suggest that persistent hyperglycemia worsens ischemic cerebral injury. Several clinical trials have shown a correlation between increased morbidity and mortality and high serum glucose levels, almost like a dose-response relationship. Animal models suggest that hyperglycemia at onset of ischemic cerebral injury carries grave prognosis. Thus, careful monitoring of serum glucose levels, for hypo and hyperglycemia, and timely therapeutic intervention will prevent extension of injury. Furthermore, elevated glucose concentration may increase production of lactic acid in ischemic tissue. This may be corrected by insulin therapy. Fluid and Electrolyte Management Stroke patients should have a balanced fluid and electrolyte status to avoid plasma volume contraction, raised hematocrit and impairment of rheologic properties of the blood (‘sludging’). In the presence of raised intracerebral pressure, a slightly negative fluid balance ( about 300-500 ml negative balance daily) is usually recommended. The electrolytes should be monitored daily and substituted accordingly. Apollo Medicine, Vol.1, September 2004
RECOMMENDATIONS FOR CENTERS OFFERING THROMBOLYSIS 1. Intravenous rt PA (0.9mg/kg: maximum 90 mg) with 10% 46
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reduction in stroke recurrence rates, this was almost always counterbalanced by an increased number of hemorrhagic complications. In the past 10 years, no randomised studies have been performed to test the effects of early full anticoagulation with conventional heparin following acute ischemic stroke, which is still used frequently in many centers. In addition, many investigator believe that heparin is not and never will be a standard therapy for all stroke subtypes. However, they believe that high-risk patients ( such as patients with stroke associated with atrial fibrillation) should be studied separately. Such a study is not available right now, and therefore, the remaining indications for the use of acute heparin after ischemic stroke are not evidence based. Table 3 gives some indications as to when full-dose intravenous heparin may currently still be proposed.
of the dose given as a bolus followed by an infusion lasting 60 minutes is the recommended treatment within 3 hours of onset of ischemic stroke. The benefit from the use of intravenous rtPA for acute ischemic stroke beyond 3 hours onset of the symptoms is smaller, but present in selected patients. Intravenous rtPA is not recommended when the time of onset of stroke cannot be ascertained reliably. This includes persons whose strokes cannot be ascertained reliably this includes person whose strokes are recognised upon awakening. Intravenous administration of streptokinase, outside the setting of a clinical investigation, is dangerous and not indicated for the management of persons with ischemic stroke. Data on efficacy or safety of any other intravenously administered thrombolytic drugs are not available to provide a recommendation. Intra-arterial treatment of acute middle cerebral artery occlusion in a 6 hours time window using pro-urokinase results in a significantly improved outcome. Acute basilar occlusion may be treated with intra-arterial therapy in selected centers.
Usually, it is recommended to elevate the partial thromboplastin time upto twice the individual baseline. Heparin should only be given as long as it takes to decide on the appropriate secondary prevention. Contraindications for the treatment with haparin include large infarcts ( e.g., more than 50% of MCA territory), uncontrollable arterial hypertension and advanced microvascular changes in the brain. Hemodilution [10,11]
Defibrinogenating Enzymes
Isovolemic hemodilution that lowers the hematocrit by 15% or more results in reduction in blood viscosity and improvements CBF [15,16]. Several large clinical trials of isovolemic hemodilution were unable to demonstrate a decline in mortality or disability with treatment. Hypervolemic hemodilution has been examined in small randomised trials with conflicting results. The clinical benefit of hemodilution therapy has not been established, and the possibility of excess brain edema has not been excluded.
Ancrod, a defibrinogenating enzyme has been shown to improve outcome after acute ischemic stroke if given within 3 hours after stroke onset and over 5 days. Recently, a European trial testing ancrod treatment in a 6 hours time window has been terminated prematurely. Platelet Inhibitors The results of two very large randomised, non-blinded intervention studies indicate that aspirin given within 48 hours after stroke ( ICT, CAST) seems to reduce mortality and rate of recurrent stroke minimally, but statistically significantly. Whether the mild positive effect of early aspirin is due to an effect on the infarct itself or due to prevention of recurrent infarction is not yet clear. It may be discussed that the NTN anti-inflammatory effect of aspirin may also influence the overall result [13].
Neuroprotection Not a single neuroprotective agent has been shown to
TABLE 3. Remaining indications for heparin treatment after stroke. • Stroke due to cardiac emboli with high risk of reembolisation (artificial valves, atrial fibrillation, MI with mural thrombi, left atrial thrombosis.
Early Anticoagulation Has been used frequently in the treatment after acute ischemic stroke. Unfortunately, none of the trials that have been performed in the past years has supported the idea that early heparin may influence outcome after ischemic stroke or at least may reduce the number of recurrent strokes [14]. Several studies that used intravenous heparinoids, subcutaneous low-molecular-weight heparin or subcutaneous heparin failed to show an overall benefit of the treatment. While there was some kind of improvement in the outcome or
• Coagulopathies such as protein C and S deficiency, APC resistance. • Symptomatic dissection of extracranial arteries. • Symptomic extra-and intracranial stenoses. • Symptoms of internal carotid stenosis prior to operation. • Crescendo TIAs or stroke in progression. • Sinus venous thrombosis.
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influence the outcome after stroke. Currently, there is no recommendation to treat patients with neuroprotective drugs after ischemic stroke.
1. Administration of heparin or low-molecular - weight heparin in bedridden patients after stroke is recommended to reduce the number of DVT and pulmonary embolism. However, there is a risk of additional intracranial bleeding. 2. Infections after stroke should be treated with appropriate antibiotics. Aspiration pneumonia may be prevented by nasogastric feeding. 3. Early mobilisation is helpful to prevent numerous complications after stroke including aspiration pneumonia, DVT and decubital ulcers. 4. Administration of anticonvulsants to prevent recurrent seizure is strongly recommended. 5. Prophylactic administration of anticonvulsants to patients with recent stroke who have not had seizures is not recommended.
Recommendations 1. There is no recommendation for general use of heparin, low-molecular heparin or heparinoids after ischemic stroke. 2. Full-dose heparin may be used when there are selected indications such as atrial fibrillation, other cardiac sources with high risk of re-embolism, arterial dissection or highgrade arterial stenosis. 3. Aspirin (100-300 mg per day) may be given after stroke to an unselected population, even without CT scan. 4. Hemodilutin therapy is not presently recommended for the management of patients with acute ischemic stroke. 5. Currently, there is no recommendation to treat patients with neuroprotective substance of the ischemic stroke.
Reduction of Increased Intracranial Pressure and Cerebral Edema The head should be elevated by 30 degree in case of raised intracranial pressure ( ICP). Intubation and hyperventilation to keep partial pressure of CO2 to 25-30 mmHg would be helpful in cases associated with increasing drowsiness. In hypertensive crisis (Blood pressure >240/130 mmHg), sodium nitroprusside is advocated but parenteral use of betablockers with IV atropine and frusemide are preferred. The blood pressure should be carefully monitored and never precipitately lowered. In the first week of massive cerebral infarction with evidence of fluid retention, dehydration with hyperosmolar solution (e.g., IV mannitol) is often tried to reduce vasogenic brain edema, but its effect is short-lasting and rebound cerebral edema may prove harmful. Furthermore, in subjects with incipient left ventricular failure, such agents can precipitate pulmonary edema. High doses of corticosteroids (dexamethasone 24-40 mg/day in divided doses parenterally) can reduce vasogenic cerebral edema, but their routine use in treatment of ischemic strokes is doubtful [11].
Prevention and treatment of complications. Acute stroke predisposes to medical complications such as pneumonia, urinary tract infections, malnutrition and volume depletion. Patients may also suffer from DVT and pulmonary embolism. Early supportive care and monitoring of physiological parameters may prevent such complications. This is best done in a dedicated stroke unit with experienced staff and early mobilisation. Immobility may lead to infections, contractions and decubital ulcers. Pulmonary Embolism and DVT Prevention of acute pulmonary embolism is of major importance in the care of every patient with stroke. Pulmonary embolism is the cause of death in upto 25% of patients dying following ischemic cerebral infarction, even in patients who otherwise would have had an excellent recovery from the stroke. The risk of DVT and pulmonary embolism can be reduced by early mobilisation and by the use of subcutaneous heparin or low-molecular weight heparin. However, this effect seems to be counter-balanced by an increase in hemorrhagic complications. Prophylaxis with subcutaneous low-dose heparin, 7,500-10,000 IU every 12 hours has been recommended for stroke patients. Pneumatic compression stockings are recommended for patients restricted to their bed, as they can further decrease the risk of DVT. Tachypnea and pain are sensitive sign of pulmonary embolism (and of pneumonia). Since chest pain and dyspnea will occur in 7080% of those patients with documented pulmonary embolism, nurses and physicians should be attentive to these signs. Examination of lower extremities should be performed daily to detect signs of DVT. Physical therapy and support stockings are suggestive as alternatives. Apollo Medicine, Vol.1, September 2004
Summary
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Safe and effective treatment is now available for patients with acute ischemic strokes. Intravenous thrombolysis with rtPA is safe and improves outcome if treatment is initiated within three hours after the onset of symptoms.
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Inttra-arterial revascularisation may provide more complete restitution of flow in the middle cerebral artery than intravenous thrombolytic therapy.
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Intra-arterial therapy may also improve the clinical outcome if it can be undertaken within the first six hours after the onset of symptoms.
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Antithrombotic drugs lessen the likelihood of deep-vein
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thrombosis and aspirin offers a moderate benefit in the prevention of recurrent stroke.
in acute stroke: Relation to stroke severity, infarct size, mortality and outcome. Lancet 1996; 347: 422-425.
Advances in the understanding of the rehabilitation process and its implementation will continue to produce improvements in both short-term and long-term quality of life among patients who survive a stroke.
9. Schwab S, Spranger M, Aschoff A, et al. Brain temperature monitoring and modulation in patients with severe MCA infarction. Neurology 1997; 48: 762-767. 10. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European cooperative acute stroke study. JAMA 1995; 274: 1017-1025.
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11. Dalal PM. Thrombolytic therapy in ischaemic stroke. Neurol India 1997; 45: 127-131.
2. Warlow CP. Epidemiology of stroke. Lancet 1998; 352: ( Suppl. III), 1-6.
12. del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Insvestigators. Prolyse in Acute Cerebral Thromboembolism. Stroke 1998; 29: 4-11.
3. Dalal PM. Strokes in young and elderly: risk factors and strategies for stroke prevention. JAPI 1997; 45: 125-131. Also in Indian J Med Res 1997; 106: 325-332. 4. Dalal PM. Ischaemic strokes : early intensive treatment. In ‘Medicine update’ ( APICON - 98) Vol.8 Supplement Das AK (ed.) All India Press, Pondicherry. 1998; 82-92.
13. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischaemic stroke. Stroke 2000; 31: 1240. 14. International stroke trial collaborative group (IST). A randomized trial of aspirin, heparin, both or neither among 19,435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569-1581.
5. Dalal PM. Neurological complications of cardiac interventions. In: Reviews in Neurology 2000. 6. Bath F; Bath P. Blood pressure in acute stroke collaboration. Cerebrovasc Dis 1997; 7: 205-213.
15. Scandinavian stroke study group. Multicentre trial of hemodilution in acute ischaemic stroke-1. Result of sub group analyses. Stroke 1988; 19: 464-471.
7. Boiser JC, Lichtman J, Cerese J, et al. Treatment of hypertension in acute ischaemic stroke: the university health consortium stroke benchmarking project. Stroke 1998; 29: 305.
16. Italian acute stroke group. Hemodilution in acute stroke. Lancet 1988; 1: 318.
8. Reith J, Jorgensen S, Pedersen PM, et al: Body temperature
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