Treatment of Acute Ischemic Stroke
Part II: Neuroprotection and Medical Management
Recanalization is the primary focus during the first hours after onset of ischemic stroke. However, preservation or neuroprotection of ischemic brain tissue by other means, prevention of stroke complications such as pneumonia and deep venous thrombosis, maximization of neural function of the surviving brain, and the start of therapies to prevent recurrent stroke are also important treatment goals. Part II of this review of acute stroke therapy focuses on these important elements of stroke care.
Neuroprotection: Hypothermia as a Model Therapy
Neuroprotective agents have been extensively tested in randomized trials of acute ischemic stroke, and no agent has been proven effective, despite promising results in animal models.1–3⇓⇓ The principle of neuroprotection after global brain ischemia, however, was recently demonstrated in 2 published trials of rapidly applied hypothermia in patients who had been resuscitated after cardiac arrest.4,5⇓ In an Australian study,4 77 patients were randomly assigned to treatment with normothermia or hypothermia (core body temperature reduction to 33°C) within 2 hours after the return of spontaneous circulation and maintained at the temperature for 12 hours. Hypothermia was started in the field by the paramedics, and the core temperature was decreased by 1.4° during the first 120 minutes after restoration of spontaneous circulation. The odds ratio for a good outcome was 5.25 (95% confidence interval [CI] 1.47 to 18.76). There were no significant differences in the frequency of adverse events.
The second study randomized 275 patients who had been successfully resuscitated from a cardiac arrest to normothermia or hypothermia (32° to 34°C) over 24 hours.5 The median interval between restoration of circulation and initiation of cooling was 105 minutes. The likelihood of a favorable outcome at 6 months in the hypothermia group (55%) was significantly better than that for the normothermia group (39%, risk ratio 1.40; 95% CI 1.08 to 1.81). The mortality rate was also significantly lower in the hypothermia group.
In a very small, nonrandomized small trial of patients with large cerebral ischemic strokes, Schwab et al6 showed that mild hypothermia with a brain temperature between 33° and 35°C may be safe and may reduce the mortality rate in this group of patients. Several methods of inducing hypothermia are currently being tested in feasibility trials. They include external cooling devices and transvascular cooling methods. Phase I studies are underway.
The results of hypothermia in the setting of resuscitation after cardiac arrest are promising for treatment of acute ischemic stroke. The Australian Trial, although smaller, seems to have had the best results, with therapy started within 30 to 60 minutes after resuscitation in most patients and a lowering of core body temperature by 1.4°C within 2 hours. These results occurred in patients who had restoration of spontaneous circulation and brain perfusion. If hypothermia is to be a successful strategy in stroke patients, it will likely need to be initiated within 2 hours of onset of stroke. Even with early initiation, hypothermia may still prove to be ineffective unless circulation is restored to the ischemic brain spontaneously or by recanalization therapy.
Treatment of Elevated Intracranial Pressure and Brain Edema
Although studies of neuroprotection have yet to provide a proven therapy for acute ischemic stroke, treatment of ischemic brain edema and preservation of the surviving brain in patients with large brain infarcts is a critical part of acute stroke therapy and can be life-saving.
Ischemic brain edema occurs during the first 24 to 48 hours after ischemic infarcts. In younger patients with complete malignant middle cerebral artery (MCA) infarction, brain edema and elevated intracranial pressure (ICP) may become a major complication and may lead to herniation and death.7 Herniation in young patients with large strokes is more common than in elderly patients because young brains often have little atrophy and thus little available space to accommodate a swollen brain in a fixed cranial cavity. These patients usually show a rapid decline in consciousness and develop the signs of herniation within 2 to 4 days after onset of symptoms. Outcome is fatal in the majority of these patients, with a mortality rate of about 80% with standard treatment.7,8⇓
Treatment of ischemic brain edema includes osmotherapy, hyperventilation, hypothermia, barbiturates, and decompressive surgery. None of these therapies have been conclusively demonstrated to be effective in improving outcome as part of a randomized clinical trial. Several phase I randomized studies are ongoing.
Intravenous infusion of substances that increase osmolality of blood create an osmotic gradient across the blood brain barrier. After this gradient, water is removed from the brain. An intact blood brain barrier is essential for this mechanism. Otherwise, the infused substance may enter brain parenchyma and may result in a rebound phenomenon if the infusion of osmotherapeutics is abruptly discontinued. Osmotic agents that are most frequently used and have been best investigated include intravenous mannitol and intravenous or enterally administered glycerol. Volume overload, hemolysis, lactic acidosis, and electrolyte disturbances are problems encountered with glycerol-based osmotherapy. During glycerol treatment, glucose infusions should be reduced. Both renal function and central venous pressure must be watched carefully in patients with underlying cardiac disease.
Electrolyte disturbance and hypovolemia are complications of osmotherapy with mannitol. During osmotherapy, plasma osmolality should not exceed 330 mOsm/kg. Short-term increases of osmolality seem to be more effective in reducing ICP compared with continuous high osmolality. Osmotherapy is only effective for 48 to 72 hours.
Conservative treatment of increased ICP in acute ischemic stroke includes hyperventilation with continuous mandatory ventilation. The arterial Pco2 is kept between 30 and 35 mm Hg. Unfortunately, the effects of hyperventilation do not last longer than 12 to 36 hours. High positive end-expiratory pressure levels may increase the already increased intracranial pressure. Tolerance of ventilatory support is achieved by potent opioid analgesics and benzodiazepines. Ketamine and volatile anesthetics should not be used because they can elevate ICP. ICP may increase during tracheal suction. The use of short-acting neuromuscular blocking agents (for example vecuronium bromide, 2 to 4 mg IV) can help to avoid this complication.
Intravenous barbiturates (eg, pentobarbital or thiopental) can decrease ICP by lowering cerebral blood volume. Frequently, a parallel decrease in mean arterial pressure leads to a decrease in cerebral perfusion pressure. Therefore, an effective therapy with barbiturates depends on a reliable on-line monitoring of ICP and mean arterial pressure. During the injection of barbiturates, it is recommended that an ECG be recorded with superficial adhesive skull electrodes. The injection of barbiturates is stopped when a burst-suppression pattern is reached. Barbiturates work for a short period. Once the vasoconstriction effect is exhausted, no further lowering of ICP can be expected.
Decompressive surgery involves removal of a large part of the hemi-cranium to allow space for expansion of edematous brain tissue. The rationale of decompressive surgery is to allow expansion of edematous brain tissue to reduce intracranial pressure and prevent fatal brain herniation, increase perfusion pressure to the brain that is still salvageable, and preserve cerebral blood flow by preventing further compression of the collateral vessels. In prospective case series, surgical decompressive therapy in a hemispheric space-occupying infarction lowers the mortality rate from 80% to 30% without increasing the rate of severely disabled survivors as compared with historical controls.7,9⇓ An ongoing pilot prospective, multicenter National Institute of Neurological Disorders and Stroke (NINDS)-funded study HEmicraniectomy And Durotomy for Deterioration From Infarction Relating Swelling Trial (HEADDFIRST) is designed to test the hypothesis that this approach improves patient outcome among patients with large cerebral infarctions.
Decompressive surgery is considered the treatment of choice of a large space-occupying cerebellar infarction with brain stem compression, although the scientific basis for this is by no means any more solid than that for hemispheric infarction. Comatose patients with large space-occupying cerebellar infarctions have a mortality rate of about 80% if treated conservatively. This high mortality rate can be lowered to <30% if decompressive surgery is performed.10,11⇓ As in space-occupying supratentorial infarction, the operation should be performed before signs of herniation are present. The prognosis among survivors is very good, even if they were comatose when the operation was performed. It should be noted, however, that these results are from small or medium-sized case series. Data from a controlled, randomized trial are lacking.
Stroke care should take place in a stroke unit. A stroke unit is a hospital unit or part of a hospital unit that focuses on the care of stroke patients. The staff and the multidisciplinary approach to treatment and care characterize the stroke unit. The core disciplines of such a multidisciplinary team are expert medical care, nursing, physiotherapy, occupational therapy, speech and language therapy, and social work.
A meta-analysis by the Stroke Unit Trialists’ Collaboration12 showed that stroke unit care was associated with a reduction in the odds of death recorded at final follow-up (median 1 year; odds ratio 0.83; 95% CI 0.71 to 0.97).12 The odds of death or institutionalized care were lower (0.76; 95% CI 0.65 to 0.90), as were death or dependency at final review (odds ratio 0.75; 95% CI 0.65 to 0.87). Subgroup analyses showed that the observed benefits were independent of patient age, sex, stroke severity, and types of stroke unit organization. There was no indication that organized stroke unit care resulted in increased hospital stay, although there was heterogeneity between the trials. In a large randomized Norwegian trial of patients treated in the acute and subacute state,13,14⇓ mortality was reduced by 46% compared with general ward treatment.
Stroke units fall into several categories. The acute stroke unit admits patients quickly and continues treatment for several days but usually less than 1 week until transfer to another rehabilitation facility, nursing facility, or home. The combined acute and rehabilitation stroke unit admits patients quickly and continues treatment and rehabilitation for several weeks or months if necessary. The rehabilitation stroke unit admits patients from an acute care hospital after a delay of 1 or 2 weeks and continues treatment and rehabilitation for several weeks or months if necessary. A mobile stroke team is a mobile team that offers stroke care and treatment to stroke patients at a variety of wards. Such teams are usually established in hospitals where stroke units are not available.
Of these various units, only the combined acute and rehabilitation stroke unit and the rehabilitation stroke unit have proven to be effective in terms of reduced mortality and handicap.15–17⇓⇓ Nevertheless, in several countries with an established rehabilitation network, emphasis has been put on hyperacute, short-term treatment in a stroke unit. This approach has not been prospectively tested in a randomized trial.
Antithrombotic Therapy and Early Secondary Prevention
The combined results of 2 very large, randomized, unblinded intervention studies indicate that aspirin given within 48 hours after stroke reduces the risk of recurrent stroke (7 per 1000 patients treated) and death without further stroke (4 per 1000 patients treated).18–20⇓⇓
Early Anticoagulation With Heparin or Heparin Compounds
For many years, early full-dose anticoagulation was used frequently in the treatment after acute ischemic stroke. This practice has changed substantially during the past 5 years because of the number of randomized trials of heparin and heparinoid compounds during the past 5 to 10 years that have shown adverse results.18,21–28⇓⇓⇓⇓⇓⇓⇓⇓ For example, in the International Stroke Study, full-dose subcutaneous heparin was compared with aspirin in patients with acute ischemic stroke.18 Although heparin was associated with a very small reduction in the recurrence rate of ischemic stroke as compared with aspirin, this was counterbalanced by an increased number of hemorrhagic complications. Another randomized study compared full-dose subcutaneous dalteparin (low-molecular heparin) with 160 mg of aspirin in patients with acute ischemic stroke who had atrial fibrillation. Patients treated with dalteparin fared similarly to those treated with aspirin.24
In the Trial of ORG 10172 in Acute Stroke Treatment (TOAST),28 patients treated with low-molecular-weight heparin fared similarly to those treated with aspirin. The subgroup of patients with documented high-grade occlusive disease of the carotid artery in the distribution of ischemia who received low-molecular-weight heparin, however, did better than those treated with aspirin.29 This post-hoc subgroup analysis has yet to be evaluated in a subsequent study.
Low-dose subcutaneous heparin or low-molecular weight heparin remains an effective treatment for prevention of deep venous thrombosis in nonambulatory patients with ischemic stroke.21 Clinical trial data that clearly support the use of full-dose heparin or heparinoid compounds in patients with ischemic stroke are lacking, however. Potential indications that may have some foundation include patients with mild or transient focal brain ischemia with high-grade carotid stenosis prior to carotid endarterectomy or patients with mild focal brain ischemia and atrial fibrillation who are subsequent candidates for subsequent oral warfarin. Table 1 gives some indications about whether full-dose intravenous heparin or subcutaneous low-molecular-weight heparin may be considered.
Currently, the only scientifically proven indication for superiority of warfarin therapy after acute ischemic stroke is for stroke patients with atrial fibrillation.30 For patients with a moderate to large infarction, warfarin therapy may be delayed for several weeks to decrease the risk of hemorrhagic transformation of the infarction. Stroke patients with another clear cardiac source of embolism, such as a mechanical valve, left ventricular aneurysm, etc, are also reasonable candidates for warfarin. For patients without a clear cardioembolic cause of cerebral infarction, the Warfarin-Aspirin Recurrent Stroke Study (WARSS) demonstrated no difference between 325 mg of daily aspirin and warfarin (therapeutic range of international normalized ratio of 1.4 to 2.8) in the prevention of recurrent ischemic stroke or death, nor was there a difference in the rate of major hemorrhage.31 For these patients without a cardiac source of stroke, however, the cost and difficulty of use for warfarin therapy in clinical practice exceeds that for antiplatelet agents. Thus, antiplatelet agents are the initial drugs of choice for secondary prevention in patients without a cardiac source of their stroke.
The choice of antiplatelet medication for subsequent stroke prevention is beyond the scope of the current article. Antiplatelet agents with proven effectiveness for prevention of recurrent stroke include aspirin 50 to 325 mg once a day, Plavix (Bristol-Myers Squibb; clopidogrel 75 mg once a day), Aggrenox (Boehringer Ingelheim; combined 25 mg of aspirin and 200 mg of slow-release dipyridamole twice a day), and Ticlid (Roche Pharmaceuticals; ticlopidine 250 mg twice a day). Aspirin at 75 mg to 325 mg is a good first choice for patients who are not on any antiplatelet medication at the time of their stroke. Warfarin should be considered for patients with a clear cardiac source of emboli, such as atrial fibrillation.
In patients treated with thrombolytic agents, neither antiplatelet agents nor heparin and heparinoid compounds should be given for 24 hours.32,33⇓ Low-dose intravenous or subcutaneous heparin or heparinoid compounds are effective treatments for prevention of deep venous thrombosis.
Other Treatments for Secondary Prevention
Agents to lower blood pressure have emerged as a new potential means to decrease the risk of recurrent stroke.34–36⇓⇓ Blood pressure–lowering agents should be used very carefully, however, if at all, in the first days after an acute ischemic stroke because overaggressive therapy can lower brain perfusion to ischemic brain tissue. Over the succeeding weeks and months, lowering of blood pressure by angiotensin-converting enzyme inhibitors and diuretics are an important new means for the prevention of recurrent stroke.
Statin agents also hold promise as a means to decrease the risk of recurrent stroke.37–39⇓⇓ If and when to begin a statin agent after an acute ischemic stroke is still under study in several ongoing trials. Certainly, in patients with clear hyperlipidemia and/or coronary artery disease, statin agents can decrease the risk of subsequent vascular events. Finally, every effort should be made, while the stroke patient is still in the hospital, to encourage cessation of cigarette smoking.
General Stroke Treatment and Prevention of Complications
General stroke treatment is the treatment of general physiological conditions that need to be optimized in the setting of an acute stroke. The other main area of stroke treatment is the treatment of complications that may be either neurological (such as secondary hemorrhage, space occupying edema, seizures) or medical (such as infections, decubitus ulcers, deep venous thrombosis, or pulmonary embolism).
General Stroke Treatment
In most stroke patients, the acute neurological symptoms are prominent, but treatment and prognosis are codetermined by underlying and associated systemic diseases that are almost always present. There is a consensus that management of general medical problems is the basis for stroke treatment.40,41⇓ General management of stroke patients comprises respiratory and cardiac care, fluid and metabolic management, blood pressure control, and treatment of elevated intracranial pressure. In addition, treatment of seizures and prophylactic measures concerning deep venous thrombosis, pulmonary embolism, aspiration pneumonia, other infections, and decubitus ulcer are part of the general treatment of the patients (Table 2).
Most authors agree that adequate treatment and preservation of vital functions constitute the basis of all therapeutic measures in acute stroke not only in stroke units but also on normal wards. On the other hand, one has to keep in mind that even the proposed management of hypertension or hyperglycemia in stroke patients has never been tested prospectively. Several excellent summaries of guidelines for general stroke care, prevention of poststroke complications, and the use of thrombolytic therapies are available, including the American Heart Association guidelines.32,33,40,41⇓⇓⇓ Four important web sites containing useful information regarding stroke protocols, sample order sets, and consensus statements include the Brain Attack Coalition page42 sponsored by the NINDS Stroke Division, the American Heart Association web site, 43 the National Stroke Association home page,44 and the web site of the European Stroke Initiative,45 the common organ of the European Neurological Society (ENS), the European Federation of Neurological Society (EFNS), and the European Stroke Council (ESC).
This is Part II of a 2-part article. Part I appeared in the September 17, 2002, issue of the journal (Circulation. 2002;106:1563– 1569).
- ↵Grotta J. Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke. 2002; 33: 306–307.
- ↵Lees K. Neuroprotection is unlikely to be effective in humans using current trial designs: an opposing view. Stroke. 2002; 33: 308–309.
- ↵Schwab S, Schwarz S, Spranger M, et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke. 1998; 29: 2461–2466.
- ↵Schwab S, Steiner T, Aschoff A, et al. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke. 1998; 29: 1888–1893.
- ↵Krieger D, Busse O, Schramm J, et al. German-Austrian space occupying cerebellar infarction study. J Neurol. 1992; 239: 47–49.
- ↵Heros RC. Surgical treatment of cerebellar infarction. Stroke. 1992; 23: 937–938.
- ↵Ronning OM, Guldvog B. Stroke unit versus general medical wards, II: neurological deficits and activities of daily living: a quasi-randomized controlled trial. Stroke. 1998; 29: 586–590.
- ↵Ronning O, M, Guldvog B. Stroke units versus general medical wards, I: twelve- and eighteen-month survival: a randomized, controlled trial. Stroke. 1998; 29: 58–62.
- ↵Indredavik B, Bakke F, Slordahl SA, et al. Stroke unit treatment improves long-term quality of life: a randomized controlled trial. Stroke. 1998; 29: 895–899.
- ↵Langhorne P, Stott DJ, Robertson L, et al. Medical complications after stroke: a multicenter study. Stroke. 2000; 31: 1223–1229.
- ↵Langhorne P, Duncan P. Does the organization of postacute stroke care really matter? Stroke. 2001; 32: 268–274.
- ↵Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke. 2000; 31: 1240–1249.
- ↵Diener HC, Ringelstein EB, von Kummer R, et al. Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Therapy of Patients With Acute Stroke (TOPAS) Investigators. Stroke. 2001; 32: 22–29.
- ↵Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials. Stroke. 2000; 31: 1770–1778.
- ↵Feigin VL, Doronin BM, Popova TF, et al. Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. 2001; 8: 81–85.
- ↵Adams HP, Bendixen BH, Leira E, et al. Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999; 53: 122–125.
- ↵Mohr JP, Thompson JLP, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2002; 345: 1444–1451.
- ↵Adams H Jr, Brott T, Furlan A, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation. 1996; 94: 1167–1174.
- ↵Marler JR, Lyden PD. The NINDS t-PA for Acute Stroke Protocol. In: Lyden PD, ed. Thrombolytic Therapy for Stroke. Totawa, NJ: Humana Press Inc; 2001: 297–308.
- ↵Byington RP, Davis BR, Plehn JF, et al. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001; 103: 387–392.
- ↵Adams HP Jr, Brott TG, Crowell RM, et al. Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association Stroke. 1994; 25: 901–1914.
- ↵NINDS. The Brain Attack Coalition. Available at: http://www.Stroke-site.org. Accessed July 15, 2002.
- ↵American Heart Association web site. Available at: http://www. americanheart.org. Accessed July 15, 2002.
- ↵National Stroke Association web site. Available at: http://www. stroke.org. Accessed July 15, 2002.
- ↵European Neurological Society, the European Federation of Neurological Society, and the European Stroke Council. The European Stroke Initiative. Available at: http://www.EUSI-stroke.com. Accessed July 15, 2002.