Medical management of stroke
The author: Professor Yasser Metwally
GENERAL MANAGEMENT OF STROKE
Stroke is diagnosed 400,000 times yearly in the United States and contributes to approximately 150,000 deaths. The vast majority of strokes are ischemic in origin. Atherothrombotic or thromboembolic arterial occlusions account for approximately 85% of all strokes. Despite substantial declines in incidence and mortality since the early 1970s, stroke ranks as the third leading cause of death in much of the industrialized world and one of the most common causes of long-term disability.
Despite a burgeoning knowledge in stroke pathophysiology, 176, 201, currently no generally accepted specific medical treatment exists for acute focal brain ischemia. Most current forms of therapy are designed to reduce complications of a recent stroke or prevent recurrences. One of the critical factors affecting outcome in the management of acute cerebral ischemia is the delay in initiating therapy.
The brain’s response to acute ischemia is influenced by the severity and duration of the insult. Experimental stroke models suggest that there are different ischemic thresholds for cerebral dysfunction and cell death. Normal cerebral blood flow (CBF) is approximately 50 to 55 mL/100 g/min. When blood flow drops to about 18 mL/100 g/min, the brain has reached the threshold for synaptic transmission failure. Although these cells are not functioning normally, they do have the potential for recovery. The second level, known as the threshold for membrane pump failure, occurs when blood flow drops to about 8 mL/100 g/min. Cell death can result. The difference between these two blood flow levels (8 to 18 mL/100 g/min) has led to the concept of a perifocal ischemic region, or ischemic penumbra, in which there is loss of the EEG and flat evoked potentials but normal ATP and extracellular concentrations of k+, 8,217 Nonfunctioning cerebral tissue adjacent to an area of cerebral infarction may be salvageable or may progress to an infarction. The potential for salvage of the ischemic penumbra is currently under intense investigation.
It is not clear how long after the onset of ischemia cerebral function can be preserved. It is possible that some function can be salvaged after severe ischemia as long as 1 hour in duration. 99 It is possible, however, that in the ischemic penumbra a more protracted insult may be sustained before tissue destruction ensues. Knowledge of different ischemic thresholds has led to the notion that acute focal brain ischemia, such as that with acute myocardial ischemia, represents a medical emergency.
KEYS TO MANAGEMENT
Diagnosis and management in the first few hours of acute focal brain ischemic symptoms are critical. 29 All patients with acute focal brain ischemia should be admitted to the hospital for evaluation and treatment. This is best accomplished in an intensive care or stroke unit, where close nursing and medical observation are possible. Management must be individualized and based on careful clinical and radiologic assessment. Diagnosis depends on a detailed history, clinical examination, and special examinations such as cranial CT. CT is critical to help differentiate a hemorrhagic from a nonhemorrhagic stroke. However, CT is only a supplement and not a substitute for a correct clinical diagnosis of ischemic stroke.
Routine laboratory evaluation should include a complete blood count with differential, platelet count, prothrombin time, partial thromboplastin time, erythrocyte sedimentation rate, serum glucose, blood urea nitrogen, serum creatinine, and serum sodium, potassium, chloride, carbon dioxide, cholesterol, triglycerides, lipoprotein electrophoresis, and VDRL test. Urinalysis, ECG, and chest roentgenography should also be performed. The physical examination should include cardiac, neurologic, and neurovascular examination. 31
SUPPORTIVE/ANCILLARY TREATMENT
The airway of an obtunded patient should be protected. Some critically ill patients need ventilatory assistance. If the patient is comatose when first seen, management of the airway and maintenance of adequate ventilation and oxygenation should be accomplished immediately. Since hypoxia can also aggravate ischemic brain damage, arterial blood gases should be evaluated and hypoxia corrected. The benefit of routine administration of supplemental oxygen remains unsettled. Aspiration and atelectasis should be prevented. Pneumonia frequently complicates stroke, 113, 155, 160 and is a leading cause of mortality in the second to fourth weeks following cerebral infarction. 203
Cerebral autoregulation is lost during acute focal brain ischemia. 241 The blood pressure should be measured frequently during the first few days after cerebral ischemia. Transient blood pressure elevation following acute cerebral infarction and normalization over days without treatment are common. 231 Mild to moderate arterial hypertension may be compensatory, and rapid lowering of the blood pressure is generally not recommended. 26, 114, 249 It is important to remember that many patients who have sustained an ischemic insult are chronic hypertensives whose cerebral autoregulation is maintained at higher levels than in normotensives.
Blood pressure reduction must be accomplished carefully to avoid exacerbating cerebral ischemia by reducing CBF too fast or too much. It is imperative to treat the blood pressure elevation only if vital organs are compromised, the diastolic blood pressure rises to 120 to 130 mm Hg or greater, or cerebral ischemia is secondary to aortic dissection. 127, 209 Blood pressure reduction must be judiciously achieved. A minimum cerebral perfusion pressure of approximately 50 to 60 torr is needed.
Patients with acute focal brain ischemia need careful management of fluids and electrolytes. 112 High serum glucose levels result in increased anaerobic metabolism, increased lactic acid production in ischemic brain tissue, and cellular acidosis. 63, 175 An intravenous access line should be placed with the infusion of half-normal or normal saline, depending on the cardiovascular status. Daily administration of fluids should be approximately 2000 to 2500 mL/ 24 h for most patients. If fluids need to be restricted because of a large cerebral infarction or mass effect due to cerebral edema, the reduction should be modest, to about 1500 mL/24 hr. Despite current controversy, we avoid hypotonic solutions or fluids containing glucose.
Prevention of complications in patients with acute ischemic stroke is the first stage of rehabilitation. The skin pressure areas are regularly examined for early signs of breakdown. The patient’s position should be checked at least every 2 hours to avoid decubitus ulcers. Alternating pressure mattresses, water mattresses, or rotating beds help reduce the risk of developing decubitus ulcers. The position of the patient’s head should be adjusted according to the clinical circumstances: In cases of increased intracranial pressure, the head of the bed is elevated to a maximum of 30 degrees to promote venous drainage and reduce the potential for cerebral edema. In cases of suspected internal carotid artery or basilar artery occlusion, patients are nursed flat in bed in order to minimize hemodynamic cerebral hypoperfusion.
Patients are generally not allowed to eat for the first 24 hours, and perhaps longer if they have difficulty swallowing. Evaluation of swallowing difficulties with detailed fluoroscopic studies is recommended. Nasogastric feedings are often necessary. Some patients require a gastrostomy or prolonged parenteral nutrition. Urinary bladder dysfunction may follow a stroke, 119, 225. Indwelling urinary catheters are associated with urinary tract infections. Incontinent or comatose patients should be catheterized, preferably with a condom catheter in men or a closed Foley catheter in women. Progressive abdominal distention in the absence of mechanical obstruction may indicate the development of colonic pseudo-obstruction; cecostomy may be required. 180
Venous thromboembolism is a common complication in patients with acute ischemic stroke. In the absence of prophylactic measures, deep vein thrombosis develops in about 33% to 75% of patients with dense hemiplegia, and lethal pulmonary embolism occurs in less than 3%. 43, 140, 233 Prevention of deep venous thrombosis may be attempted with pressure-gradient stockings, pneumatic-compression stockings, low-dose (5000 IU twice a day) subcutaneous heparin administration, 68, 140 or low molecular weight heparinoids. 228
Seizures, most often focal, are not uncommon in the early and late phases following ischemic stroke. 22, 62, 83, 128, 200 Most post-stroke seizures can be controlled with anticonvulsant monotherapy. Depression occurs commonly in patients with stroke, especially with left hemispheric infarctions. These patients often require antidepressant medications, such as trazodone or nortriptyline. 21, 181, 182
TREATMENT OF CEREBRAL EDEMA
Edema develops in the first hours after an ischemic insult to the brain. Ischemic brain edema is initially cytotoxic and later vasogenic. 117, 122, 123, 164 The two phases of ischemic brain edema overlap. The cytotoxic phase takes place over minutes to hours and may be reversible. Cerebral edema peaks around 24 to 96 hours after an ischemic brain insult. Early signs are drowsiness, pupillary asymmetry, and periodic breathing patterns, 184. If there are signs of increased intracranial pressure and herniation, endotracheal intubation, mechanical hyperventilation, and mannitol administration are indicated. Mannitol (20% to 25% solution for infusion) is given initially in a dose of 1 g/kg body weight over 20 to 30 minutes, followed by a dose of 0.25 g/kg body weight every 4 hours, depending on clinical findings and serum osmolality. Furosemide or ethacrynic acid may be used in conjunction with mannitol. Hyperosmolar solutions of glycerol may reduce ischemic brain edema, but earlier studies of glycerol treatment produced inconsistent results, 162,137, 150, More recently, Bayer et al, 16 using intravenous glycerol in 173 patients with recent ischemic stroke in the carotid artery territory, demonstrated a reduced mortality rate at 1 week in the treated group (12%) versus the control group (30%). Corticosteroids are not useful in ischemic brain edema; both large doses and conventional doses of dexamethasone have been ineffective. 162, 163
In cases of massive nondominant cerebral hemispheric infarction (specifically, inferior division of middle cerebral artery territory infarction) with cerebral edema and herniation refractory to medical therapy, surgical decompression may be attempted as a desperate life-saving measure. 45, 79,161, In cases of cerebellar infarction with compression of posterior fossa CSF outflow structures, resection of the necrotic cerebellar tissue can be life-saving.
PHARMACOLOGIC PROTECTION
Recent investigations suggest that calcium influx into the cells plays a major role in the process of neuronal death due to ischemia. 142, 176, 202, 234 Calcium may contribute to stroke by causing vasoconstriction, enhancing platelet aggregation, and increasing brain susceptibility to ischemia. It has been proposed, therefore, that calcium channel blockers may be useful in patients with focal brain ischemia and cerebral vasospasm. The commonly used calcium channel blockers-nifedipine, verapamil, and diltiazem-are not useful.
Nimodipine, a lipophilic dihydropyridine calcium channel blocker with cerebrovasodilatory properties, has been found to increase the mean hemispheric cerebral blood flow when given to healthy volunteers. 11, 71 , 194 After a pilot study with promising results, 69 Gelmers and coworkers 72 randomized 93 patients with recent (<24 hours) ischemic strokes to 28 days of oral nimodipine (120 mg daily divided in four doses) and 93 patients to the control group. Both groups had comparable prognostic variables. All patients received a standard regimen of 10% depolymerized dextran for 12 hours daily during a period of 5 days and low-dose (5000 IU twice a day) subcutaneous heparin for deep vein thrombosis prophylaxis. Mortality was reduced with nimodipine compared with placebo (8 versus 19 deaths). In addition, neurologic outcome as measured by the Matthew Scale was improved in the nimodipine-treated group. A double- blind, multicenter study to compare the efficacy and safety of nimodipine with that of placebo in patients with recent (<48 hours) ischemic stroke has been recently completed; results are unavailable at present.
Since the discovery of opiate receptors within the central nervous system, 173, 220, it has been hypothesized that endogenous opioides may play a role in cerebral ischemia. Naloxone, an opiate receptor antagonist without agonistic action, may limit neuronal injury. Naloxone alters transmembrane calcium flux, 186, 212, affects lipid peroxidation, 124, has antioxidant actions, 135, increases cerebral blood flow when given in high concentrations, may have platelet antiaggregatory effects, 227, and may prevent cerebral edema. 236
There are as many reports of improved outcome in patients with acute stroke given naloxone as there are reports demonstrating its lack of effect. Baskin and Hosobuchil, 13, found that two patients with focal cerebral ischemia had remarkable reversal of hemiparesis following the intravenous administration of small doses of Naloxone. The observations that levels of immunoreactive beta-endorphin-like material are greater in the ischemic hemisphere than on the control side and that improvement of neurologic function follows naloxone administration to adult gerbils with carotid,artery occlusion led these authors to suggest a pathophysiologic role for endorphins and opiate receptors in cerebral ischemia. 97
Subsequent reports regarding the use of naloxone in acute stroke in experimental animals, 67, 96, 103, 116 and humans have appeared with conflicting results. Iselin and Wise, 105, noted improvement of ischemic neurologic deficits in an elderly woman with pulmonary edema who developed hemiparesis. In the study by Cutler et al, 44 patients with acute focal neurologic deficit within the previous 72 hours were treated with 0.8 to 2 mg of intravenous naloxone. The patients included 14 with ischemic strokes, 4 with intracerebral hemorrhage, and 1 with subarachnoid hemorrhage. Fifteen patients had no effect with naloxone, 2 had subjective sensory improvement, 1 worsened, and none had changes in motor performance. Fallis et al, 57, studied 15 patients with stroke of less than 60 hours duration. The patients included 14 with ischemic stroke and 1 with intracerebral hemorrhage. There was no significant response following the administration of 0.4 to 4.0 mg of intravenous naloxone. In the study by Jabaily and Davis, 0.8 to 1.2 mg of naloxone were administered to 13 patients with acute focal neurologic deficits within the previous 4 to 36 hours. The causes of the stroke syndromes included two intracerebral hemorrhages and 11 cases of cerebral ischemia with or without CT abnormalities. Three patients had neurologic improvement shortly after the administration of naloxone.
Perraro et al, 172, observed no difference in 20 patients randomized to receive naloxone at a total dose of 1.2 mg compared with 20 patients given placebo. In the study by Estanol et al, 54, there was complete and long-lasting improvement in 7 of 20 patients with acute cerebral ischemia of less than 24 hours duration and in all 3 patients who had developed ischemic complications within 10 minutes of cerebral angiography. These results contrasted sharply with the lack of effect of naloxone in 20 patients with CT-proven cerebral infarction of 7 to 14 days duration and in 5 patients with intracerebral hemorrhage of less than 24 hours duration.
Perry et al, 171, showed improvement in 2 of 5 patients given naloxone within 12 hours of onset of ischemia. Finally, Adams et al, 4, evaluated large doses of naloxone in a dose-escalation study to determine the highest reasonably tolerated dose for further human studies in 27 patients with acute focal cerebral ischemia. Patients were treated within 48 hours of stroke onset. All patients received a bolus dose followed by a 24-hour infusion for a total dose of naloxone of 52.3 to 4978 mg. The drug was well tolerated. Transient or sustained improvement was noted in 13 patients. A phase 11 study was then conducted by the same investigators in 38 consecutive patients with acute or progressing ischemic stroke. The patients were treated with a 160 mg/ml bolus, followed by an 80 mg/ml/hr infusion for 24 hours. Results of this study are not available at present. 166
The benefits of naloxone administration for a patient with acute focal brain ischemia remain unproven. Part of the apparent conflict in the literature may result from the variety of conditions used to test naloxone’s alleged protection in brain ischemia, the small total number of patients studied, and the relatively small dose used in many of the studies. 56
Barbiturates depress cerebral metabolism, increase cerebrovascular resistance, lower increased intracranial pressure, and have anticonvulsant properties, 183. Barbiturates may prevent focal ischemia, particularly if given before an ischemic insult. 183, 196 Attempts to improve prognosis after stroke with the use of barbiturates have been unsuccessful. 5, 246 Their clinical application is uncertain and cannot be recommended.
Ischemia-induced neuronal damage may be mediated by excitatory amino acid neurotransmitters, such as L-glutamate and L-aspartate. Animal studies demonstrate that, hours after an ischemic insult, levels of glutamate increase and may result in cell death. This excitotoxic cell death is blocked by N-methyl- D-aspartate (NMDA) antagonists. The value of excitatory neurotransmitter antagonists awaits corroboration by clinical trials. 19, 23, 40, 65, 75, 81, 84, 143, 168, 187 190, 204, 211 Baclofen inhibits gamma-aminobutyric acid (GABA) and the release of glutamate but fails to protect neurons from experimental ischemia in a rat model. 109, 185,
ANTITHROMBOTIC AGENTS
Anticoagulants have been prescribed in patients with acute cerebral ischemia to prevent progression of thrombosis or recurrent embolization. Guidelines for anticoagulant therapy in patients with acute ischemic stroke are not well defined. 35, 110, 174, 192, 197 The most commonly used anticoagulant in acute cerebral ischemia is heparin, a heterogeneous mixture of polysaccharides of variable molecular weight (between 4,000 and 40,000 daltons). Heparin binds to antithrombin III and enhances the rate by which this plasma-protein inhibitor can inhibit thrombin, activated Factor X (Factor Xa), and other serine proteases (IXa, Xla, and XIIA), 230. Anticoagulant therapy is not indicated in patients with completed brain infarctions.73, 198, Aggregate data of seven randomized studies Of anticoagulant therapy for completed stroke, involving 449 treated patients and 446 controls, demonstrate that mortality, severe bleeding, and lethal strokes were higher among the anticoagulant-treated group. 10, 11, 53, 94, 100, 133, 141 Heparin anticoagulation has not been found to be effective in 225 stable patients with thrombotic stroke of less than 48 hours duration (progression prior to assigned therapy or cardioembolic sources including atrial fibrillation were reasons for exclusion). Improvement in neurologic condition was noted in 26.6% of patients given heparin and 24.3% of those given placebo. Progression of neurologic signs was noted in 17% of patients given heparin and 19.5% of control patients. 51
Anticoagulant therapy appears beneficial in preventing recurrences following nonseptic cardiac embolization. 11, 198, 247, 248, The Cerebral Embolism Study Group, 43, conducted a randomized trial of intravenous heparin versus no anticoagulation in patients with recent (<48 hours) presumed cardioembotic strokes. At 14 days, among the 24 treated patients, there were no deaths, strokes, or hemorrhages, whereas there were 2 strokes and 2 deaths among the 21 controls. Unfortunately, this study was terminated prematurely owing to the presumed benefit of immediate anticoagulation with intravenous heparin.
The assertion that anticoagulation with heparin conveys protection against recurrences in the setting of acute stroke due to cardiac embolism has recently been challenged. 191
Heparin may have a role in treating progressing stroke, 153, 156, 198. Aggregate data from three randomized 1, 31,61 and three nonrandomized studies 61,154,237 suggest that heparin reduces the rate of progression in cerebral infarction. However, Dobkin et al, 49, failed to demonstrate a beneficial effect of heparin in “lacunar” stroke in progression, Haley and associates, 85, could not demonstrate a beneficial effect for intravenous heparin in patients with progressing cerebral infarction. Consequently, the value of intravenous heparin in patients with acute focal brain ischemia continues to be controversial.
Because treatment of acute focal brain ischemia with heparin can be complicated by bleeding problems or thrombocytopenia, 6, 9, 18, 38, 120, 199, 235 the safety and possible efficacy of low molecular weight heparinoids in stroke are under investigation. Low molecular weight heparinoids are an attractive alternative therapy because, despite a major antithrombotic effect, there is decreased bleeding tendency compared with heparin. Dissociation between the effect of heparin upon platelets and its anticoagulant activity can be achieved by fractionation of heparin. Low molecular weight heparins and heparinoids are sulfated polysaccharides, prepared semisynthetically by sulfation or partial degradation of heparin, or occur naturally in animal tissue. 17, 37, 58, 77, 108
One of the most extensively studied low molecular weight heparinoids is ORG 10172, which is a mixture of a low molecular weight heparin-like component (4%), low molecular weight heparin sulfate (approximately 80%), dermatan sulfate (approximately 8% to 10%), and chondroitin sulfate (about 6% to 8% ). 87, 91,119,144, 219, 228, Both heparin sulfate and dermatan sulfate have been shown to have some anticoagulant effects mediated through heparin cofactor 11, a plasma protein inhibitor that reacts only with thrombin. 224 Because the effects of ORG 10172 are not reflected by changes in the partial thromboplastin time, they are monitored by assay of plasma anti-Factor Xa activity. 218
Biller et al, 20, assessed the safety of ORG 10172 in ischemic stroke. In their study, 26 patients (14 men and 12 women) were treated within 24 hours of stroke in a dose-escalation study. Treatment was initiated with a bolus dose followed by a continuous 7-day infusion at an hourly rate of 10% of the bolus. The subtypes of strokes included 10 lacunes, 8 large artery thrombotic occlusions, 5 large artery embolic occlusions, and 3 cardiogenic emboli. After 24 hours of treatment, 14 (54%) patients had improved, 8 (31%) had remained the same, and 4 (15%) had worsened. Following 1 week of treatment, 20 (77%) had improved, 4 (15%) had worsened, and 2 (8%) had not changed. Three months after treatment, 25 patients (96%) were improved and 1 (4%) was worse. There were no deaths. Minor hemorrhagic complications during the study period occurred in three patients (mild epistaxis in one patient and heme-positive stools in two patients). No patient required treatment or discontinuation of ORG 10172. Hemorrhagic transformation of cerebral infarction was not found on CT examinations done on days 7 to 10. No significant changes in hemoglobin, platelet count, or prothrombin time occurred, nor were there any obvious dose- related trends. There was a tendency for the partial thromboplastin time to increase, in most instances within the normal range.
In their phase 11 study, Massey et al, 136, evaluated the safety and possible efficacy of large doses of ORG 10172 in 57 additional patients with recent ischemic stroke. Treatment was initiated with a bolus, followed by a rapid infusion for 4 hours, a slower infusion for the next 12 hours, and then a maintenance infusion for the remainder of the 7 days of therapy. The subtypes of stroke studied included 19 large artery thrombotic occlusions, 17 lacunes, 11 large artery embolic occlusions, 8 cardiogenic emboli, and 2 strokes of unknown etiology. After 24 hours of treatment, 27 (47%) patients had improved, 21 (37%) had not changed, and 9 (16%) had worsened. Following 1 week of treatment, 41 (72%) patients had improved, 19 (16%) had not changed, 5 (9%) had worsened, and 2 (3%) had died. Three months after completion of treatment, 40 (70%) patients had improved, 8 (14%) had not changed, 2 (3%) had worsened, and 6 (9.5%) had died. One patient was lost to follow-up. Two patients had fatal hemorrhagic transformations of large cardioembolic cerebral infarctions. Although these studies are preliminary, the authors concluded that ORG 10172 appears safe. Further studies are assessing the potential efficacy of this drug in stroke patients.
Prostacyclin (PG1,), a derivative from arachidonic acid cyclo-oxygenation, inhibits platelet aggregation and is a powerful vasodilator. 36, 159, 240 Results of the initial studies of the effectiveness of prostacyclin in ischemic stroke were encouraging. Gryglewsky et al, 82, reported rapid and dramatic improvement in motor and language deficits following the administration of intravenous prostacyclin. In their study, 10 patients (7 men and 3 women) were treated within 5 days after hospital admission. Treatment consisted of intravenous prostacyclin, 2.5 to 5.0 ng/kg/min in 6-hour intervals during 1.0 to 2.5 days. Side effects during prostacyclin administration were unusual. In the study by Miller et al, 152 seven patients (four men and three women) with acute cerebral infarction within the previous 24 hours were treated with intravenous prostacyclin for at least 24 hours (25 to 72 hours). Four patients had clinical improvement, and three either did not change or worsened. Studies of platelet function, measured by beta-thromboglobulin, normalized during prostacyclin administration.
In contrast, Martin et al, 134, found that prostacyclin afforded no benefit in 32 patients with acute cerebral infarction randomized to either prostacyclin or placebo. Two weeks after treatment, 6 patients (18%) were dead, 3 in each group. Results of a double-blind controlled trial of prostacyclin versus placebo in 26 patients with ischemic stroke were inconclusive: The therapeutic effect of prostacyclin was not sustained once the infusion was discontinued. 104, A lack of therapeutic efficacy of prostacyclin was observed by the Prostacyclin Study Group. 101, In their study, 43 patients with ischemic stroke were randomized to prostacyclin and 37 to placebo. The two groups were well matched. Eight patients (18.6%) treated with prostacyclin improved their neurologic score, compared with 10 (27%) in the placebo group. Response to treatment was either ineffective or indeterminate in 35 (81.4%) patients in the prostacyclin group, compared with 27 (72.9%) in the placebo group. To summarize, results of the open-label clinical trials of prostacyclin failed to demonstrate a beneficial effect of this therapy for patients with recent ischemic stroke.
The rationale of treatment of strokes with platelet antiaggregating drugs depends on the occurrence of platelet aggregation by both experimental and clinical studies. Thrombi that develop in areas of rapid flow, such as arteries, are particularly rich in platelets. Platelets, reacting to a damaged subendothelium by atherosclerosis, become adherent, aggregate, and release many vasoactive substances. 50 The mode of action of aspirin in preventing stroke appears to reflect inhibition of the platelet arachidonate pathway and therefore the synthesis of thromboxane A,a powerful vasoconstrictor and platelet aggregator.
Platelet antiaggregating drugs, particularly aspirin, have been shown to reduce the risk of stroke or death or both by about 30%, 232. However, it is impossible in most of the published trials to assess the value of platelet antiaggregating drugs in the first hours after cerebral infarction, when treatment is likely to be of most value. We do not have much evidence yet about the effect of platelet antiaggregating drugs in the outcome of acute ischemic stroke. The published trial results have included patients with transient ischemic attacks (TIAs), reversible ischemic neurologic deficits, and minor strokes with long intervals to therapeutic randomization. Most patients were entered within I month to 1 year of the onset of their neurologic deficit. Bousser et al, 24 evaluated the effects of aspirin alone (1000 mg daily), aspirin in combination with dipyridamole (225 mg daily), and placebo among 604 patients with either TIAs (15%) or strokes (85%) over an average of 3 years. At the end of the study, the cumulative rate of fatal and nonfatal stroke was 18% in the placebo group and 10.5% in each of the active treatment groups. However, a long-term Swedish study, in which 505 patients with recent (1 to 3 weeks) minor or major strokes were randomized to aspirin (1500 mg daily) or placebo, showed that the rate of death, myocardial infarction, recurrent stroke, or TIA was not affected by aspirin. Stroke recurrence was 13/c in the placebo group, compared with 12% in the aspirin group, 216. Ticlopidine hydrochloride is a newer platelet antiaggregant that inhibits the adenosine diphosphate in the platelet membrane. Two major recent clinical trials have shown benefits of ticlopidine, 72a, 89a. These benefits applied equally to men and women.
Although treatment with platelet antiaggregating drugs in acute ischemic stroke has not been thoroughly tested, we recommend their use in all patients with recent atherothromboembolic cerebral infarction.
THROMBOLYTIC AGENTS
Cerebral angiography, when performed in the first hours after cerebral infarction, demonstrates occlusive lesions that correlate with clinical deficits in about 80% to 90% of patients, 208. Because thrombotic and embolic arterial occlusions are the leading causes of cerebral infarction, pharmacologic therapy directed at achieving acute cerebral arterial recanalization via thrombolysis is gaining widespread attention. The ideal thrombolytic agent should be nonantigenic, inexpensive, safe, and capable of dissolving thrombi selectively.
Pharmacologic thrombolysis may re-establish blood flow in the infarct- related vessel improve flow to the ischemic penumbra, and limit the infarct size. However, pharmacologic thrombolysis does not affect the factors responsible for thrombogenesis and carries the risk of rethrombosis, distal embolization, and reperfusion tissue damage, 131, 132, including hemorrhage, 30, 206, and cerebral edema. 125
Early experience with urokinase and streptokinase in patients with ischemic stroke demonstrated a high risk of hemorrhagic complications. 1,2, 39, 46, 86, 89, 92, 138, 145,147, 149, These agents convert circulating plasminogen to plasmin and produce a systemic lytic state, increasing the risk of bleeding. The studies using these agents, however, have been the subject of a number of criticisms: 47,207 Treatment was initiated as late as 24 to 48 hours after the onset of infarction. Because these studies were completed before CT scanning was available, small hematomas could have been treated (despite clear CSF examination). The dose of thrombolytic agents administered was variable and often was combined with heparin therapy, thus introducing considerable variations into outcome data.
Because of the potential disadvantages of streptokinase and urokinase, several “clot-selective” thrombolytic agents [i.e., acylated streptokinase-plasminogen complex, single-chain urokinase-type plasminogen activator (SCU- PA), and tissue-type plasminogen activator (t-PA)], which produce local fibrinolysis and fewer systemic effects, have recently been developed, and interest in their use for the hyperacute management of cerebral ischemia has been rekindled. The safety and possible usefulness of tissue plasminogen activator are under intense investigation at this time. 28, 46
Tissue-type plasminogen activator (t-PA) is a naturally occurring thrombolysis activator with a molecular weight of approximately 70 kilodaltons which is now available for clinical use as a result of recombinant DNA technology, 229. Tissue-type plasminogen activator has several advantages as a thrombolytic agent: It has a functional half-life of about 5 minutes, compared to about 16 minutes for urokinase and 23 minutes for streptokinase 223; thus, if bleeding occurs or invasive procedures are needed, the thrombolytic action of the drug disappears shortly after the infusion is discontinued. It is clot-specific because of its high affinity for plasminogen in the presence of fibrin. This allows efficient activation of the fibrin clot without activation occurring in the plasma. It causes only a modest reduction in fibrinogen concentration compared with the reduction caused by streptokinase. It is nonantigenic and usually causes no adverse reactions other than bleeding. The overall reported incidence of intracranial bleeding in studies involving t-PA (80 to 150 mg) for acute myocardial infarction has varied from 0.0% to 1.9%. 25
HEMORHEOLOGIC TREATMENT
Modification of biorheologic factors has been postulated to provide protection in cerebral ischemia. 66, 221,243 Factors that influence the viscosity of the blood include hematocrit, fibrinogen concentration, erythrocyte aggregability, erythrocyte deformability, platelet aggregation, and shear rate. Because blood is a non-Newtonian fluid, it lacks a fixed viscosity. Lowering blood viscosity, increases cerebral blood flow. Favorable modification of biorheologic properties may be achieved by lowering hematocrit, reducing fibrinogen concentration, or increasing red blood cell deformability. High hematocrit values have been associated with increased blood viscosity, decreased cerebral blood flow, and increased infarct size. 88, 222 Despite some encouraging observations,80, 129, 247, 244, 245 the results of different hemodilution trials using isovolemic, hypovolemic, or hypervolemic paradigms do not appear to show a beneficial effect in the management of acute focal brain ischemia.
Wood and Fleisher, 242, treated nine unselected consecutive patients with acute ischemic neurologic deficits in the middle cerebral artery territory with hypervolemic hemodilution. Hemodilution was achieved by the infusion of 5% human serum albumin or dextran 40 or both within 10 minutes to 4 days after onset of ischemic symptoms. The hematocrit was reduced from 41% to 32%, the mean arterial blood pressure was lowered from 101 mm Hg to 94 mm Hg, and the central venous pressure was raised from 4 to 12 cm H 20. Eight of the nine patients improved within 24 hours after the initiation of hypervolemic hemodilution therapy, although in two patients clinical improvement was infusion dependent.
In their study, Strand et al, 213, randomized 52 patients with ischemic stroke to hemodilution and 50 to the control group. Both groups had comparable prognostic variables. Hemodilution achieved by the combination of venesection and infusion of low molecular weight dextran reduced mean hemoglobin values from 14.7 to 12.7 g/dL, reduced hematocrit values from 43% to 37%, and lowered whole blood viscosity at a shear rate of 23 sec-1 from 7.0 to 4.3 cps over the first 2 days. Eighty-five per cent of the hemodiluted patients improved their neurologic scores over the first 10 days, compared with 64% for the control group. Only 8% of the hemodiluted patients deteriorated over 10 days, compared with 26% of controls. Mortality at 10 days was 1.9% for the hemodiluted group, compared with 10% for controls. At the 3-month follow-up, hemodiluted patients ambulated better and had shorter lengths of hospitalization, but their fatality rate was only slightly less than that of the control patients (25% versus 28%).
Surprisingly, the Scandinavian Stroke Study Group, 193, subsequently found that hemodilution (using the same paradigm previously reported) provided no benefit to general patients with acute ischemic stroke of less than 48 hours duration. In this study, the investigators randomized 183 patients to hemodilution and 190 to the control group. The mean hematocrit was reduced from 44.2% to 37.1% at day 5 in the hemodilution group, whereas the mean hematocrit value was essentially unchanged in the control group. Length of hospitalization and the need for long-term institutional care were not favorably influenced by hemodilution. Furthermore, mortality at day 5 was higher (5.5%) for the hemodiluted patients than for the control group (1.6%)
The Italian Acute Stroke Study Group, 106, randomized 633 acute (<12 hours) hemispheric ischemic strokes to hemodilution and 634 to the control group. The two groups had comparable prognostic variables. Hemodilution was achieved by phlebotomy and replacement of the same volume with dextran 40 in saline solution. The mean hematocrit declined from 43% to 37% at 48 hours in the hemodiluted group. This reduction of hematocrit value was maintained for 7 days. Mortality rate was equally distributed in the two treatment groups. After 6 months of randomization, 175 patients in the hemodiluted group were dead, compared to 176 of the control group.
Finally, in another multicenter trial, the Hemodilution in Stroke Study Group, 90, randomized 45 patients with acute (<24 hours) ischemic carotid artery territory stroke to hypervolemic hemodilution with pentastarch and 43 such patients to standard therapy. Pentastarch was administered to achieve a reduction of the hematocrit value to 30% to 33% and an increase of the pulmonary wedge pressure to 15 mm Hg. There were four early fatalities secondary to cerebral edema in the hemodiluted group and one fatality in the control group. The hemodilution group, however, had twice the number of patients with severe strokes and fewer patients randomized within 12 hours.
Ancrod, a purified protein extract of Malayan pit viper venom, causes a reduction of fibrinogen levels and blood viscosity. 41,114 In addition, ancrod is thought to activate fibrinolysis. Its use may be valuable in acute cerebral ischemia. In addition, ancrod is thought to activate fibrinolysis. Its use may be valuable in acute cerebral ischemia. Hossmann et al, 99 randomized 15 patients with acute (<48 hours) ischemic stroke to ancrod in combination with low molecular weight dextran and mannitol and 15 to low molecular weight dextran and mannitol alone. Ancrod was administered subcutaneously at a dose of IU/kg body weight. The plasma fibrinogen levels were reduced to 100 to 130 mg/dL, and there was more than a 30% reduction of the apparent blood viscosity at low shear rates in the ancrod group. Neurologic outcome, measured in arbitrary units, was better in the ancrod group. After 2 weeks, 2 (13.3%) patients in the ancrod group had died, compared with 5 (33.3%) in the control group. The report by Olinger et al, l67 also suggests a beneficial effect of ancrod. Twenty patients with acute cerebral infarction received intravenous infusion of ancrod (n = 10) or placebo (n = 10) for 7 days. Ancrod therapy resulted in a reduction of mean plasma fibrinogen level from 385 mg/dL at baseline to 116 mg/dL at 6 hours and 52 mg/dL at 24 hours. Neurologic outcome was better in the ancrod group. One patient in the placebo group had a recurrent stroke within a 3-month follow-up, whereas no one in the ancrod group had a recurrence. Further studies of ancrod in acute or progressing ischemic cerebral infarction are underway.
Pentoxifylline (oxpentifylline), a methylxanthine analogue, is an active hemorheologic agent that decreases blood viscosity by increasing red blood cell deformability and decreasing fibrinogen levels. It also decreases platelet aggregability. Herskovits et al, 93, carried out a preliminary study in 66 patients suffering from recent (<30 days) TIAS. Patients were treated with either aspirin (1000 mg) and dipyridamole (150 mg) or pentoxifylline (1200 mg). The 1-year follow-up yielded a 10% TIA recurrence in the pentoxifylline group, compared with 28% in the aspirin plus dipyridamole group. The incidence of stroke was similar in both groups (4.7%), however. Pentoxifylline was more recently evaluated in a double-blind placebo-controlled parallel group in 13 centers in the United States. 102 Two hundred and ninety-seven patients with ischemic stroke were entered into the study; 151 were randomized to pentoxifylline and 146 to placebo. Pentoxifylline was given intravenously at a dose of 16 mg/kg/ day for 3 days and then orally (400 mg three times a day) for 25 days. Although there was some benefit during the first days of therapy, this was not maintained beyond the fourth day. There were 18 (12%) deaths in the pentoxifylline-treated group, compared with 15 (10%) in the placebo group.
Dextran decreases the aggregation of platelets and red blood cells, thus decreasing blood viscosity. The benefit of low molecular weight dextran in the treatment of acute ischemic stroke remains unproven. 74 , 115, 139,201 The value of perfluorocarbons (Fluosol), an artificial blood substitute capable of increasing oxygen transport and expanding plasma volume, has not been established. 137,169, 170, 215
OTHER MEDICAL THERAPIES
Aminophylline (theophylline), a methylxanthine derivative, causes vasoconstriction of normal cerebral vessels. This might shunt blood from healthy to ischemic areas, causing an inverse intracerebral steal. 55,76,205, Despite its early popularity, therapeutic results with this compound have been negative. Britton et al, 27 randomized 22 patients with acute ischemic stroke to intravenous theophylline and 24 patients to placebo. Treatment was administered for 3 days; the dose of theophylline maintained a plasma level of 55 to 110 limol/L. Mortality was 27.2% in the theophylline group, compared with 20.8% in the placebo group. All deaths were secondary to the stroke.
Despite experimental evidence that cerebral vasodilators increase cerebral blood flow, these agents are of no value and may even cause harm by producing a steal phenomenon. 42, 148, 165, 178 Observations have been made that a diet rich in eicosapentaenoic acid may account for the low incidence of cardiovascular disease in Greenland Eskimos. However eicosapentaenoic acid in the form of fish oil concentrate (MaxEpa) has not been found to be of value in stroke patients, 78. Oxygen radical formation is increased in cerebral ischemia. Because excessive formation of free radicals may cause lipid peroxidation, impaired function of cell membranes, and cell death, the potential benefit of free-radical scavengers deserves further investigation. 32,48,111
The observations that propranolol has protective effects in experimental myocardial ischemia, 132,179, and that long-term case fatality rates in patients with ischemic cerebrovascular disease are primarily due to cardiac disease 3 has led to a number of investigations into the effect of beta blockade in stroke patients. In a preliminary study, the long-term prognosis in 60 patients (36 men, 24 women) discharged on beta blockers was compared with the outcome in 60 patients (36 men, 24 women) not treated with beta blockers. The groups were matched for type of stroke (39 brain infarctions, 15 TIAS, and 6 intracerebral hemorrhages) and prior history of hypertension and cardiac disease. The follow- up, which extended to a median of 41 months, disclosed 13 (22%) deaths in the beta blocker group compared with 21 (35%) in the group without beta blockers. 111 A more pessimistic evaluation was reported by Barer et al, 12 who randomized 100 patients with acute ischemic hemispheric stroke to placebo, 101 acute stroke patients to atenolol (50 mg daily), and 101 acute stroke patients to propranolol (80 mg daily). Treatment was given for 3 weeks. After I week, 3 (3%) in the placebo group were dead, compared with 11 (10.9%) in the atenolol group and 15 (14.8%) in the propranolol group.
GM, ganglioside has been reported to be beneficial in recovery following stroke. 14, 15 Nevertheless, in a 6-month follow-up period no significant difference was observed between 27 stroke patients treated with intramuscular ganglioside GM, (100 mg) for 28 days and 26 stroke patients assigned to placebo, 95. The results of therapy with trazadone, a blocker of serotonin reuptake in the central nervous system, have not been promising, 177. Phenytoin protects the brain during periods of decreased oxygen availability, but its use in human focal cerebral ischemia has not been tested. 7
Vasopressor therapy has occasionally been recommended for the treatment of patients with cerebral ischemia. 59, 159, 238 In 1972, Wise et al, 239, reported the beneficial effect of vasopressor treatment, primarily using levophed, in 13 patients with acute focal cerebral ischemia. In that study, 5 of the 13 patients had improvement in neurologic signs after blood pressure elevation to 150 to 170 mm Hg systolic and 85 to 100 mm Hg diastolic. Despite these anecdotal reports of improved neurologic function with vasopressor drugs, this form of therapy has not gained wide acceptance, except for cases of postangiographic ischemic neurologic deficits, because of the potential risk of intracerebral hemorrhage and cardiac decompensation. 151
SUMMARY
Ischemic stroke is a major cause of death and disability. Despite its high incidence, acute management remains controversial. Most current forms of therapy are designed to reduce complications of a recent stroke or prevent recurrences. Experimental data suggest that the optimal time for intervention is the hour immediately following brain ischemia.
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