Ischaemic strokes : management in first six hours.
Cerebrovascular disease (CVD) or stroke is one of the foremost causes of high morbidity and mortality for many nations of the world, posing a major socio-economic challenge in the occupational and neuro-rehabilitational programmes of the 'stroke-survivors'. For example, in USA alone it has been estimated that a sum of 3261 million dollars is spent as direct cost for treatment, in addition to 4104 million dollars as indirect costs, consequent on economic losses of 'stroke victims'. Thus, the new concept in stroke pathophysiology and strategies for stroke prevention have assumed global importance. Among all risk factors for strokes, hypertension is one of the most important and treatable factor. Community screening surveys, by well defined WHO protocol, have shown that nearly 15% of urban population is hypertensive (160/95 mm Hg or more). Though high blood pressure has the highest attributable risk for stroke, there are many other reasons such as patient's compliance in taking medicine and poor followup in clinical practice that may lead to failure in reducing stroke mortality. In subjects, who have transient ischaemic attacks (TIAs), regular use of antiplatelet agents like aspirin is well established in prevention of stroke. It is also mandatory to prohibit tobacco use and adjust dietary habits to control body weight. Associated conditions like diabetes mellitus etc. should also be treated. It is advisable to initiate community screening surveys on well defined populations for early detection of hypertension and TIAs. Primary health care centres should be the base stations for these surveys, because data gathered from urban hospitals will not truly reflect the crude prevalence rates for the community to design practical prevention programmes.
The term stroke defines rapidly developing clinical symptoms and signs of focal, and at times global, loss of cerebral function lasting more than 24 hours, or leading to death, with no apparent cause other than of vascular origin. The ischaemic stroke refers to a vascular insufficiency (thrombo-embolism) rather than haemorrhage. Stroke is the third most common cause of death in developed nations and a worldwide problem, where nearly 4.5 million persons die from stroke each year. About 80% of all acute ischaemic strokes are from cerebral infarction and 10% of them die within 30 days. Among the stroke-survivors, almost 50% will experience some disability. The main goals of therapy are to rapidly restore and maintain adequate blood supply to ischaemic tissue with aim to minimise brain damage, and thereby neurologic deficit and disability, and improve quality of life after stroke.
Current demographic trends suggest that the Indian population will survive through the peak years of occurrence of stroke (age 55-65 yrs) and strokesurvivors in the elderly with varying degree of residual disability will be a major medical problem. The available data from community surveys from different regions of India for 'hemiplegia' presumed to be of vascular origin, indicate a crude prevalence rate in the range of 200 per 100,000 persons. Thus, the anticipated costs of rehabilitation of 'stroke-victims' will pose enormous socio-economic burden on our meagre health-care resources, similar to what is now faced by industrialised nations in the West. Therefore, early diagnosis, intensive treatment and prevention of strokes at any age should be our main strategy in the national health planning.
Basic Considerations in Ischaemic -Hypoxic Cerebral Injury
The normal functions of the brain are dependent upon a relatively constant supply of oxygen and glucose, as well as other nutrients derived from the blood perfusing it (55 to 70 ml of blood per 100 g of brain per min). The principal source of energy is almost exclusively oxidation of glucose. If for any reason, the blood flow is critically reduced below 15 ml per 100 g per min, the resulting ischaemia with hypoxia when sufficiently prolonged, may cause death of neurones and glia (cerebral infarction). Brain cells (neurons and glial cells) require constant supply of oxygen for normal function. The brain receives about 25% of the body's oxygen supply, but it cannot store oxygen; a reduction of blood flow for even a few minutes can be highly disastrous. Researchers are working to elucidate the cycle of events involved in cell injury or death after oxygen is deprived.
The mean arterial blood pressure, cerebrovascular and tissue resistance, local metabolic products (pH, PaO2, PaCO2 tension, etc.) together with several known and unknown factors, help to maintain critical threshold of blood flow for energy metabolism.
Furthermore, the blood flow varies in different areas of brain and self-regulatory mechanisms ('autoregulation') govern the regional flow to meet local metabolic needs. For example, with an increase in partial pressure of CO2, the arterioles dilate to increase blood flow. The precise role of vasoconstrictor (sympathetic) and vasodilator nerve impulses in the regulation of vascular tone and local blood flow is much debated. The circulating neurochemical transmitters (serotonin, catecholamines etc.) however, do modify the local needs. Conversely, in the zone of cerebral ischaemia, there is paralysis of autoregulation and microvasculature. This area is almost non-reactive to pressure changes, to vasoactive agents and to other forms of stimuli. The cerebral vasculature in this region becomes permeable to protein and fluid leaks in the vicinity (extracellular cerebral oedema). Such events also lead to local haemoconcentration and vascular stasis. Thus, cerebral injury is not the sole result of disturbances in perfusion of cerebral microvasculature, but an endresult of a series of highly complex ischaemichypoxia modifying events.,
Recent studies on molecular and metabolic events leading to cerebral injuries have shown that there is a dense central core, surrounded by a less dense zone of ischaemia (penumbra). Neuronal death occurs in this central focus, unless perfusion is quickly restored. On the other hand, cells in the zone of penumbra remain viable for atleast three hours (therapeutic window) and may be salvaged by reperfusion or neuroprotective agents, to prevent further damage. Major factors, which enhance nerve cell injury are an increase in intracellular cytosolic calcium concentration (from failure of ionic pump functions or 'leaks'), changes in Na/K gradients, acidosis, release of glutamate as well as 'excitotoxic' substances, free radicals, and many unknown factors which in turn disrupt the blood brain barrier (BBB) and cell membrane functions, predisposing to cell death. Here, energy depletion from ischaemic-hypoxia is one of the key events that fails to maintain normal concentrations of cellular adenosine triphosphate (ATP) leading to delay in resynthesis of macromolecular proteins essential for cell structure. Such energy failures also induce proteolysis and lypolysis in addition to production of arachidonic acid, platelet activating factors, free radicals etc. causing further neuronal damage (ischaemic cascade hypothesis). Thus, severity of cerebral injury is not mere a result of hypoxia from impaired perfusion but end-result of several highly complex 'ischaemia-modifying factors'. The role of leucocyte-endothelial interaction, receptor activation, post-ischaemic hypo/hyper perfusion damage ('reperfusion injury'), nitric oxide, nerve growth factors and gene expression are under study.,
To protect the brain from such haemodynamic ischaemic insult, nature has provided several collateral pathways. The four major extracranial arteries (one pair each of carotid and vertebral arteries), carrying oxygenated blood from the aortic arch, form a good caliber, low resistence anastomoses (the circle of Willis) at the base of the brain. In addition, extracranial anastomoses between the cervical branches of the ipsilateral external carotid, subclavian and vertebral arteries have also been identified. These arterial anastomoses help to maintain cerebral blood supply in individuals even with occlusion of a major artery in the neck. Likewise, large precapillary anastomoses exist between anterior, middle and posterior cerebral arteries and various cerebellar arteries. Such post-willisian anastomoses further protect cerebral tissue from the effects of occlusion of single cortical branches. Thus, in an individual with symmetrical circle of Willis, despite major extracranial arterial occlusions, sufficient blood may still reach the ischaemic-hypoxic territory through collateral pathways to prevent impending cerebral insult. On the other hand, in the presence of generalised arterial disease (atherosclerosis), congenital variations and multiple skipped stenotic lesions, these collateral pathways may prove inadequate in maintaining normal blood flow and thereby predispose to cerebral injury or infarction.
Treatment of Ischaemic Cerebrovascular Disease
Inspite of rapid progress in the management and prevention of cerebrovascular disease (CVD), ischaemic and haemorrhagic strokes still represent a major cause of morbidity and mortality. Experimental studies and clinical trials during the last two decades have contributed greatly to our understanding on pathophysiology of various stroke lesions and therapeutic interventional strategies in the management. The Siriraj stroke score (SSS) which helps in clinical differentiation of haemorrhagic strokes from ischaemic strokes, having an overall accuracy of 90 percent is shown in [Table I]. An outline of diagnostic evaluation and the emergency management of an acute stroke case (acute hemiplegic syndrome) is described in [Table II].
The goal of therapy is to avoid development of brain infarction and, if already present, to prevent its progression or recurrence. Treatment is divided into three phases : Phase I - saving life and speeding recovery; Phase II - rehabilitation to achieve adaptation (physical, occupations, social, etc. ) for a gainful employment; and Phase III- measures to prevent recurrence of stroke are advocated.
General Measures in Prevention of Medical Complications in Stroke : In a multicentre study, Langhorne et al recorded medical complications in 265 (85%) of 311 consecutive stroke patients. These include:chest infections (22%), urinary tract infection (241) other infections (19%), pressure sores (21%), anxiety-depression (16%), falls with serious injury (5%), thrombo-embolism (2%), in addition to neurologic sequelae like recurrent stroke (9%), epileptic seizures (3%) and confusional states (over 25%). The aim of treatment during Phase I of acute cerebral ischaemia (ASCI) is to prevent above complications. The maintenance of vital signs (temperature, pulse, respiration, blood pressure), patency of airway, fluid and electrolyte balance, and prevention of complications like pulmonary aspiration, seizures,thrombophlebitis, bedsores, etc. are mandatory. Here, general medical and meticulous nursing care are of paramount importance. Unless there are major cardio-pulmonary problems, in the acute stage head-low or flat position in bed is preferred. On account of loss of 'cerebral auto regulation', the regional cerebral blood flow (rCBF) is often reduced in the head-up position and this effect is more evident in vertebro-basilar territory lesions. If recline position is adopted, the patient should be frequently turned from side to side to prevent hypostatic congestion and bedsores. The role of intensive stroke-care units for specialised care of 'stroke-victims' is now greatly emphasised, to achieve early hospital discharge and home based rehabilitation as cost-effective management.,
Ventilation : In acute brain injury, hypoxia predisposes to cerebral oedema, raised intracranial pressure and may precipitate herniation. In presence of drowsy or stuporous state, hypoventilation or pulmonary aspirations leading to cerebral hypoxia is a frequent hazard. Thus, every effort should be made to keep the airway patent and prevent accidental aspirations by gentle care of pulmonary secretions. Ventilatory support may be indicated when blood oxygen saturation falls below 90% with raised PaCO2.
Here, administration of oxygen (4 to 6 litres per minute) through an oxygen tent rather than nasal catheter is routinely advocated. Pulmonary secretions should be aspirated with utmost sterile precautions.
In comatose subjects, having signs of cerebral hypoxia secondary to hypoventilation, artificial respiratory support through an endotrachial tube, to maintain blood gases within the normal range, is strongly recommended. It should be noted that patients ventilatory needs are very difficult to predict in terms of lung compliance, airway pressure changes and inspiratory flow needs, because their breathing pattern fluctuates with progression of neuro-deficit.
Furthermore, the use of heat and moisture exchangers with hygroscopic properties, as well as bacterial/viral filters, near the face mask are more desirable to maintain humidification and sterile atmosphere. For long term ventilatory support tracheostomy rather than endotrachial tube would be ideal.,
Blood Pressure : In acute stroke, 'cerebral autoregulation' is lost and blood flow in the infarcted areas is solely dependent on mean arterial BP. In presence of severe hypertension (e.g. BP over 220/120 mmHg) parenteral therapy with titratable agents such as i.v. labetalol or 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 strokesubjects often fall unpredictably within 24 hours to few days; which may hamper perfusion in zone of ischaemic penumbra leading to irreversible injury. Therefore, any significant hypotensive episode should be promptly treated to prevent extension of cerebral infarction. However, the correct management of blood pressure in acute stroke is still debated., There is radical rethinking that 'isolated systolic hypertension in elderly' is a distinct clinical entity and will require management to reduce the relative risk of cardiovascular events. Likewise, uncontrolled blood pressure among the hypertensive patients receiving irregular treatment is a major problem associated with increase in incidence of preventable strokes. 
Cardiac Arrhythmias : In acute cerebrovascular accident, it is not unusual to find irregular pulse and ECG changes suggestive of myocardial ischaemia. Diphenyl hydantoin sodium (100 mg two or three times a day) is frequently prescribed for premature beats of frequent occurrence. However, atrial or ventricular tachyarrhythmias should be appropriately treated. Anticoagulant drugs are commonly administered to prevent further embolisation., Bradyarrhythmias are not uncommon and may point to raised intracranial pressure or cerebral oedema which will demand prompt therapy (e.g. parenteral frusemide or 100 ml bolus dose of mannitol). For incipient left ventricular failure or congestive cardiac failure, cardiac glycosides are routinely used, and decongestive measures (salt and fluid restriction, diuretics etc.) are advocated.
Body Temperature : Low body temperature or induced hypothermia reduces the oxygen demand and may help vulnerable neurones in ischaemic zone, but this form of therapy is not routinely practised.
Conversely, rise in body temperature will raise cerebral oxygen consumption and metabolic demands., Fever secondary to infection is treated with appropriate antibacterial therapy. Pyrexia of central origin (e.g. pontine lesions) is managed with agents like paracetamol or analgin. Experimental hypothermia is neuroprotective in brain ischaemia. However, the value of lowering the core temperature by antipyretics, narcotics, barbiturates, ice water enemata etc.) is not established. This may however, prove helpful in critical situations.
Fluid and Electrolyte Balance : Ischaemic tissue with break in the 'blood-brain barrier' (BBB) retain fluid, predisposing to cerebral oedema. Thus, a phenomenon of 'cerebral squeeze' sets in which compresses the adjacent viable neuronal tissue. The swollen brain may also herniate transtentorially onto the vital brainstem areas and thereby impair level of responsiveness and increase neurologic deficit. Hence, parenteral 5% dextrose in water should be avoided in early stages of acute cerebral infarction with brain swelling. Judicious restriction of fluid intake (oral/parenteral) during first 48 to 96 hours or even a negative fluid balance is beneficial. On the other hand, excessive diuresis may produce haemoconcentration, and even a state of cerebral hyponatraemia, thereby potentially worsening cerebral perfusion in the borderline zones of ischaemia. Estimation of serum osmolality, electrolyte content, blood gas parameters and haematocrit will help in correcting hemo-concentration, hyponatraemia, acidosis, etc. before irreversible neuronal damage sets in.
Serum Glucose : Experimental models suggest that persistent hyperglycaemia worsens ischaemic 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 hyperglycaemia at onset of ischaemic cerebral injury carries grave prognosis. Thus, careful monitoring of serum glucose levels, for hypo and hyperglycaemia, and timely therapeutic intervention will prevent extension of injury. Furthermore, elevated glucose concentration may increase production of lactic acid in ischaemic tissue. This may be corrected by insulin therapy.
Therapeutic Measures to Improve Cerebral Blood Flow : The aim of treatment is to increase cerebral perfusion after stabilisation of cardiac functions and to prevent further thrombo embolic episodes. Hyperviscosity should be treated by isovolaemic haemodilution. Haematocrit is one of the chief determinants of whole-blood viscosity. It is postulated that lowering the haematocrit value to 30 to 33 percent with haemodilution therapy improves CBF and oxygenation of infarcted tissues. Isovolaemic or hypovolaemic haemodilution with low-molecular-weight dextran or hydroxyethyl starch or 5 percent albumin infusion with or without phlebotomy is often considered. Such treatment should be carefully monitored in subjects with cardiovascular disease and in those at risk of developing cerebral oedema. The duration of therapy varies from a minimum of 72 hours to a maximum of 5 to 7 days. However, results of recent randomised trials have failed to show consistent beneficial effects of haemodilution therapy.,
Reduction of Increased Intracranial Pressure and Cerebral Oedema : The head should be elevated by 30o in case of raised intracranial pressure (ICP). Intubation and hyperventilation to keep partial pressure of CO2 at 25 to 30 mmHg would be helpful in cases associated with increasing drowsiness. In hypertensive crisis (BP>240/l30 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 precipitantly 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 oedema, but its effect is short-lasting and rebound cerebral oedema may prove harmful. Furthermore, in subjects with incipient left ventricular failure, such agents can precipitate pulmonary oedema. High doses of corticosteroids (dexamethasone 24-40 mg/day in divided doses parenterally) can reduce vasogenic cerebral oedema, but their routine use in treatment of ischaemic strokes is doubtful.
Asprin (Acetyl salicylic acid) prevents platelet adhesion/aggregation by blocking production of platelet derived thromboxane A2 but suppresses the release of prostacyclin from vascular endothelium. It is widely used in primary and secondary prevention of strokes., In treatment of TIA/RIND and in secondary prevention of strokes, the optimal dose is still debated but results based on recent studies indicate that low dose therapy (100 mg/day or less) may be as effective as higher dose (325 mg/day or more). A combined analysis of 40,000 randomised patients with acute stroke showed a significant reduction of 7 per 1000 in recurrent ischaemic stroke (1.6% for aspirin against 2.3% for controls, 2P < 0.00001); haemorrhagic transformation of original infarct occurred in 1% of treated versus 0.8% of placebo group (2P = 0.07). The reviewers concluded that 'early aspirin is of benefit for a wide range of patients, and its prompt use should be routinely considered for all patients with suspected acute ischaemic stroke, mainly to reduce the risk of early recurrence'. They also noted that of the 9000 patients (22%) who were randomised without a prior CT scan, aspirin appeared to show net benefit 'with no unusual excess of haemorrhagic stroke'; moreover, even among the 800 (2%) who had inadvertently been randomised after a haemorrhagic stroke, there was no evidence of net hazard (further stroke or death: 63 in aspirin group versus 67 in control)'.
Other antiplatelet drugs like sulfinpyrazone or dipyridamole used alone do not offer any specific advantage. In the ESPS2 study it was recommended that combination of asprin (50 mg) and dipyridamole (200 mg BD) has additive benefit due to synergisic activity.
Ticlopidine (thienopyridine derivative), a platelet antiaggregant, inhibits platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid, thrombin and platelet aggragating factors (PAF). It also reduces plasma fibrinogen and increases red cell deformability. lt has shown more than 30% reduction in the 'stroke risk' in patients as compared to aspirin therapy. It is equally beneficial to men and women. Subjects with diabetes mellitus, those on antihypertensives and those with elevated creatinine levels benefit more with ticlopidine than aspirin. Well controlled trials have shown consistent positive benefit with reduction in non-fatal and fatal events in heart, brain and peripheral arteries. It is useful in the prevention of recurrence of both macro and micro vascular episodes. However, the drug is expensive and relatively toxic (i.e. reversible neutropaenia and diarrhoea are some of the known side-effects); hence, routine haematological check up is necessary during therapy.
Thienopyridines (ticlopidine and clopidogrel) are reported to be more effective than aspirin in preventing serious vascular events in high risk subjects. In four randomized trials of 22,656 patients having TIA/ischaemic stroke, thienopyridines were found to reduce the odds ratio of a vascular event by 9% (odds ratio 0.91; Cl 0.84-0.98; 2P=0.01) preventing 11 events per 1000 patients so treated.
Clopidogrel (Plavix) appears safer than ticlopidine but it is still more expensive. Newer antiplatelet agents like Abciximab are potent antagonists of platelet glycoprotein IIb/IIIa and appear to be safe when administered upto 24 hours after acute ischaemic stroke (CT/MRI confirmed). At 3 months, there was a trend towards higher rate of minimal residual disability, by Barthel and Modified Rankin Scale, among patients receiving Abciximab as compared to placebo group.
Parenteral heparin and long-term oral anticoagulants have been extensively tried in acute ischaemic strokes. Though such treatment can prevent extension of thrombus, its value in completed stroke is doubtful and its use is often fraught with dangers. On the other hand, in recurrent TIAs, thrombosis in-evolution, cardio-embolic strokes with valvular or nonvalvular atrial fibrillation,, subjects not responding to platelet antiaggregants and in deep venous thrombosis or pulmonary embolism, judicious use of anticoagulants is often advocated.
In International Stroke Trial (1ST), 19,435 patients within 48 hours of acute ischaemic stroke received 14 day treatment with 5000 units (U) heparin twice daily, or 12500 U heparin twice daily and no heparin, and each of these three groups received no aspirin or 300 mg of aspirin per day. In the final analysis of death or non- fatal recurrent stroke, there was no added advantage in the group who received heparin treatment.
To minimise the risk of haemorrhagic complications, it is necessary that the ischaemic infarction is confirmed by investigations like CT scan and CSF and not on the basis of clinical acumen alone. The value of diffusion weighted imaging (DWI) and magnetic resonance angiography (MRA) in acute ischaemic stroke substantially improves the accuracy of diagnosis of stroke sub-type. In one study, pre MRI diagnosis matched the final diagnosis in only 48%, but this improved further to 83% by DWI studies and upto 94% with DWI/MRA studies. Thus, the diagnostic usefulness of DWI and MRA is superior to CT scan alone, and almost mandatory in trials of thrombolytic therapy in hyperacute ischaemic stroke.
During the stage of heparinisation, thromboplastin time (aPTT) is kept upto 2.0 times the control, and 3000 to 5000 units of heparin are often given on 6 to 8 hourly basis. In absence of automatic infusion pumps, in practice, an intravenous bolus of 100 units/kg body weight followed by continuous infusion (1000 units per hour for 24 hours) under constant supervision preferably in an acute care unit is advocated. Coumadin sodium (2 to 5 mg/day) is generally well tolerated anticoagulant drugs. Prothrombin time is ideally maintained around INR of 2.0 to 3.0. Newer synthetic short chain heparins or heparinoids ( ORG 10172) are reported to be safer and effective but cost-prohibitive.
Recurrent cerebral embolisation, increasing focal or global brain oedema, pale infarct turning into haemorrhagic one, bleeding within an infiltrating neoplasm and enlarging subdural haematoma can all be misdiagnosed as a 'progressive stroke'. If subject worsens under anticoagulant therapy, diagnostic reevaluation should be done and a second CT or MRI scanning with or without CSF examination (under manometric control) may have to be carried out to ascertain the accuracy of diagnosis and cause of worsening. Active bleeding ulcers, haemorrhagic diathesis, malignant hypertension, hepatic failure, drug allergy and patient's poor compliance, are considered major contraindications to anticoagulant therapy.
Cerebral ischaemia induces release of excitatory aminoacid neuro transmitters like glutamate and glycine which promote calcium entry into neurons through receptor mediated membrane channels (e.g. N-methyl-D-aspartate [NMDA] and alpha amino-3-hydroxy-5-methyl-4-isoazole propionic acid [AMPA] channels). Cell destruction most likely occurs from production of nitric oxide and subsequent formation of other free radicals. NMDA channel has atleast six sites which may be blocked by Lubeluzole, Cerestat, Citicoline, CGS-19755, MK-801, HA-966, etc. Enzymatic inhibition of nitric oxide synthetase by N-nitro-L-arginine also appears to protect against glutamate neurotoxicity but efficacy of these agents in humans awaits further clinical trials.
Voltage dependent calcium channel antagonists (dihydropyridine compound 'nimodipine') are drugs which have cytoprotective action in ischaemic stroke. By and large, to obtain the best results, therapy should be started within 6 to 8 hours of ischaemic insult (i.e. within the 'therapeutic window' oral nimodipine 120 mg/day). The American nimodipine study group found that nimodipine had no overall beneficial effect when treatment was started within 48 hours; but there was definite benefit if therapy began within 18 hours of ictus in CT negative cases. As dihydro-pyridine compounds produce hypotension, blood pressure should be constantly monitored and the concurrent use of serotonin depletors (e.g. reserpine) and alpha blockers which may cause postural hypotension should be avoided., In experimental models, GV150526 - a selective glycine site antagonist reduces infarct volume in focal cerebral ischaemia. Preliminary randomized studies are encouraging but results of ongoing trials (GAIN 2) are awaited. On the other hand, further studies on neuroprotective effect of an NMDA antagonist 'Selfotel' have been suspended on account of neurotoxicity.
Spontaneous recanalisation with better survival by intrinsic thrombolysis is well documented. Increasing experience with several 'clot-selective' thrombolytic agents (acylated streptokinase-plasminogen complex, single chain urokinase type plasminogen activator [SCUPA], etc.) and recombinant plasminogen activator (e.g. Prourokinase) have demonstrated significant and sustained neurological improvement when treatment is initiated within the first few hours of ictus (MRI positive and CT negative ischaemic infarct), i.e. when 'window of therapeutic opportunity' is open.
Intravenous Thrombolytic Therapy : The European cooperative acute stroke study (ECASS), a multicentric randomised double blind placebo controlled trial, where rt-PA (recombinent tissue activator of plasminogen) was given in the dose of 1.1 mg/kg t-PA intravenously within 3-6 hours of acute hemispheric ischaemic CVD (without major signs of early infarct on initial CT) involved 620 patients with moderate to severe deficit. 109 cases (17.4%) were excluded for violation of protocol. The remaining patients were divided in two sub-groups: (i) target population (TP) and (ii) intention-to-treat (ITT) respectively. The scales of functional invalidity (Barthel index and Modified Rankin Scale) at 90 days were chosen as primary end-points and a combination of above scales plus score of neurologic deficit (the National Institute of Health Stroke Scale- NIHSS as well as the Scandinavian stroke scale), duration of hospital stay and case-fatality ratio were considered as secondary endpoints. In this study, TP group showed a significant favourable effect on primary end-point indicating benefit of early treatment but this efficacy was limited only to a defined subgroup with highly specific criteria of early infarct by CT.,
National institute of neurological disorders and stroke (NINDS) rt-PA Stroke Study Group (1995) involved a multicentric trial on 624 patients where rt-PA was given in dose of 0.9 mg/kg within three hours of onset of acute cerebral ischaemia (by specific CT criteria). Significant improvement was not achieved in neurological score (NIHSS) within the first 24 hours, but post 3 month analysis of functional score (Barthel index, Modified Rankin Scale) favoured rt-PA group. The NINDS and ECASS trials showed that thrombolysis with rt-PA within 3 hours can be an effective treatment in acute ischaemic stroke and nearly 30 percent patients are likely to have none or minimal disability at 3 months assessment as compared to placebo group [Table III].,
On the other hand, the risk of intracerebral haemorrhage following thrombolytic therapy rises after 3 hours, and particularly more with streptokinase. Clinical trials on streptokinase therapy, namely: Multicenter Acute Stroke Trial-Europe (MAST-E), Australian Strepto-kinase Trial (ASK) and Multicenter Acute Stroke Trial-Italy (MAST-I) have all been terminated for reasons of safety.,, In these studies thrombolytic agent was given IV within 4-6 hours of clinical onset of stroke irrespective of its severity (e.g. 9 percent of MAST-I patients were comatose); and except for absence of haemorrhagic infarct by initial CT, other restrictive radiological criteria were not enforced. In the MAST-E study, haemorrhagic transformation was more frequent and unacceptable in treatment group as against placebo arm. In MAST-I study, the treatment group had high mortality at 6 months period. In ASK study, functional outcome was significantly unfavourable, particularly in patients receiving streptokinase after 3 hours of onset of stroke.,, Furthermore, inaccurate prehospital diagnosis by ill-defined CT criteria was probably responsible for false-positive assessment in nearly 25% of cases. For examples, severe hypoglycaemia can mimic a stroke and can be lifethreatening if not treated promptly and correctly. Therefore, diffusion and perfusion MR imaging within 0-6 hours of hyperacute ischaemic stroke is considered almost mandatory.
Subsequently, ECASS-II trial was planned similar to NINCDS study within 6 hours of acute ischaemic stroke using 0.9 mg/kg alteplase, enforcing strict neuroradiological exclusion criteria. Here, 40.3% (165 patients) in alteplase-group and 36.6% (143 patients) in the placebo-group had favourable outcome. These results do not confirm statistical benefits for alteplase. Symptomatic intracranial haemorrhage occurred in 8.8% (36 patients) receiving alteplase as against 3.4% (13 patients) in the placebo group. Another placebo-controlled double-blind study in 142 subjects on rtPA found 'no significant rtPA benefit on any of the planned efficacy end-points at 30 and 90 days in patients treated between 0 and 6 hours after stroke onset'. Thus, controversy on efficacy of alteplase between 3 to 6 hours of acute ischaemic stroke continues.
Intraarterial Thrombolytic Therapy in Acute Cerebral Ischaemia : Success of thrombolytic therapy depends on early recanalisation and effective reperfusion in the zone of ischaemic penumbra with an objective to salvage viable neuronal tissue within 'therapeutic time window' (i.e. within 1-3 hours). Recent advances in superselective microcatheter (Tracker-18 or microsoft stream catheter) techniques permit the investigator to reach the exact site of occlusive lesion and infuse a thrombolytic agent directly on to the clot surface thereby achieving higher rate of successful recanalisation. However, reperfusion rate is variable and less effective for proximal carotid lesions (12%) as compared to middle cerebral lesions (45 to 80%).[42-44] Successful thrombolysis in vertebro-basilar occlusion has been reported with survival in 14 out of 19 patients, and favourable outcome in 10. All 24 patients where the occlusion persisted died (p=0.000007). Similar encouraging results have been reported by other centres.,
The favourable results of PROACT-I study have been reconfirmed by randomized controlled PROACT-II trial with favourable outcome in 40% of r-proUK patients as against 25% of controls. Recanalisation was achieved in 66% of treated group and 18% of control group (p=0.001) but intracranial haemorrhages were noted in 10% of treated group versus 2% of the controls (p=0.06). Results of placebo controlled randomized trials are awaited. At present, intraarterial thrombolytic therapy appears possible only in a select subgroup of patients within 3 hours of onset of ischaemic stroke, satisfying strict neuroradiological exclusion criteria to prevent misdiagnosis; and at centres where specialised teams of neurologists and neuroradiologists are available to monitor recanalisation and reperfusion by transcranial doppler evaluation and by diffusion and perfusion MRI studies.,
In three large randomized study comparisions (GISSI-2, ISIS-3 and GUSTO-1) of acute myocardial infarction patients treated with thrombolytic therapy (streptokinase versus t-PA), 9.4% of cases receiving i.v. streptokinase and 9.2% of subjects on t-PA based regimens had developed 'stroke or death'. Thus, the fundamental question remains unanswered on cardiovascular advantage of more intensive thrombolytic therapy versus the occurrence of stroke or death as a disadvantage ?,
It is doubtful that rt-PA by itself will constitute the magic answer to devastating consequences of ischaemic stroke and that the basic optimal medical care still remains the sheet-anchor of overall medical management of acute ischaemic stroke.
Parenteral pentoxyfylline (300 mg/IV/day) has beneficial effect on impaired red cell function and fluidity. Its influence on pathologically altered reactivity of platelets as well as hypofibrinolysis may therefore demonstrate clinically relevant antithrombotic properties. In presence of abnormal haemorheology, long-term oral therapy is often practiced. Prostacyclin and fish oil therapies are still under trial stage and not routinely advocated. Use of barbiturate induced coma in treatment of ischaemic strokes has been of doubtful value. It has been postulated that metabolism of ischaemic neurones is suppressed and thereby helps to preserve them. A controlled trial of intravenous glycerol infusion in acute strokes has demonstrated reduced mortality in treated patients, probably due to reduction in cerebral oedema. Novel pharmacological approaches on use of endothelial receptors, second generation glutamate inhibitors, calpain inhibitors, cytokines and chemokines, oxygenated fluorocarbon nutrient emulsion (OFNE), enzyme inhibitors and genetherapy, are in the experimental stage.
Thromboendarterectomy with or without reconstructive vascular surgery within a few hours or days after an acute ischaemic brain infarction is considered risky, because early reperfusion may convert pale infarct into a haemorrhagic one. However, encouraging results are not uncommon in selected cases.
Recent well-designed controlled studies (NASCET, ECST), have confirmed beneficial results of endarterectomy in tight cervical stenosis (70-99%). It has been observed that there is 17% absolute and 35% relative risk reduction for ipsilateral stroke and stroke death if endarterectomy is combined with best medical care. Patients who benefit the most from surgery are those with highest risk-factors. During immediate post-operative period, higher doses of aspirin and control of all risk factors are mandatory. The benefit by carotid endarterectomy in symptomatic lesions with mild stenosis (30-69%) or in asymptomatic cases for patients with recent (within 120 days) hemispheric or retinal TIA's or nondisabling strokes is controversial., In a recent report, the NASCET group observed that: 'The risk of stroke among patients with asymptomatic carotidartery stenosis is relatively low. Forty-five percent of strokes in patients with asymptomatic stenosis of 60 to 99 percent are attributable to lacunes or cardioembolism. These observations have implications for the use of endarterectomy in asymptomatic patients. Without analysis of the risk of stroke according to cause, the absolute benefit associated with endarterectomy may be overestimated. On the other hand, irregularity of plaque surface at all degrees of stenosis is a major stroke risk factor. Similar views that: 'the decision whether or not to operate in asymptomatic patient should be based on available data on risk associated with degree of stenosis and the activity of atheromatous carotid lesion in addition to issues of medical and surgical morbidity'. Thus, many centres would allow surgery if the plaque is irregular and actively embolising distally despite moderate (70%) stenosis. The risk of stroke is significantly greater with carotid angioplasty than with carotid endarterectomy., At present, carotid angioplasty is not recommended for the majority of patients with symptomatic carotid artery disease. Nevertheless, percutaneous angioplasty with stent has been successfully tried in treatment of inaccessible distal carotid or middle cerebral and vertebro-basilar lesions. The results of controlled trials are awaited.
Neuro-rehabilitation : As soon as subject shows signs of neuronal recovery with some volitional movements, active physiotherapeutic measures should be started for early rehabilitation.
Stroke prevention : Modification of risk-factors has shown the decline in stroke morbidity and mortality. Among the modifiable risk factors, control of hypertension is most important. One overview of 14 randomised trials showed a 40% reduction in stroke risk in patients able to lower their diastolic blood pressure by more than 6 mm of Hg.
Smoking seems to be dose related. Light smokers are twice at risk, where as heavy smokers are four times at risk compared to general population. Thus, tobacco use should be prohibited. In diabetic subjects, stroke is probably secondary to microvascular disease and atherogenesis. TIA precedes stroke in 10% to 14% of cases. Here, prophylactic platelet antiaggregant therapy (aspirin 325 mg/day) is beneficial. In TIA cases, having symptomatic carotid stenosis (70-99%), endarterectomy is currently advocated. The cardiovascular diseases with or without atrial
fibrillation (especially secondary to rheumatic heart disease), coronary artery disease, recent myocardial infarction and mitral valve prolapse are other well documented risk factors. A variety of haematological abnormalities (e.g. increase or decrease in levels of haemoglobin, protein C and S deficiencies, elevated fibrinogen and lupus anticoagulant/anticardiolipin antibodies, etc.) have been shown to corrlate with higher incidence of strokes. Most studies find a relationship between elevated lipids and atherosclerosis in both coronary and carotid arteries. The role of regular physical exercise and keeping ideal body weight needs no emphasis.,,,
I am highly greatful to D. V.R. Bhimani, Executive Vice President of L.K.M.M. Trust Research Centre at Lilavati Hospital, for unstinted support at all satges.