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Stroke
Treatment
Use of ramipril in preventing stroke: double blind randomised trial.
1
Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, Davies R, Ostergren J, Probstfield J; HOPE Investigators. Heart outcomes prevention evaluation.
Canadian Cardiovascular Collaboration, McMaster University, 237 Barton St E, Hamilton, ON, Canada L8L 2X2. jackie@ccc.mcmaster.ca
BMJ. 2002 Mar 23;324(7339):699.
OBJECTIVE: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke. DESIGN: Randomised controlled trial with 2x2 factorial design. SETTING: 267 hospitals in 19 countries. PARTICIPANTS: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study. OUTCOME MEASURES: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study. RESULTS: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment. CONCLUSION: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure.
Source: PubMed
A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke.
Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP Jr, Jackson CM, Pullicino P; Warfarin-Aspirin Recurrent Stroke Study Group.
Neurological Institute, Columbia Presbyterian Medical Center, New York, NY 10032, USA. jpm10@columbia.edu
N Engl J Med. 2001 Nov 15;345(20):1444-51.
BACKGROUND: Despite the use of antiplatelet agents, usually aspirin, in patients who have had an ischemic stroke, there is still a substantial rate of recurrence. Therefore, we investigated whether warfarin, which is effective and superior to aspirin in the prevention of cardiogenic embolism, would also prove superior in the prevention of recurrent ischemic stroke in patients with a prior noncardioembolic ischemic stroke. METHODS: In a multicenter, double-blind, randomized trial, we compared the effect of warfarin (at a dose adjusted to produce an international normalized ratio of 1.4 to 2.8) and that of aspirin (325 mg per day) on the combined primary end point of recurrent ischemic stroke or death from any cause within two years. RESULTS: The two randomized study groups were similar with respect to base-line risk factors. In the intention-to-treat analysis, no significant differences were found between the treatment groups in any of the outcomes measured. The primary end point of death or recurrent ischemic stroke was reached by 196 of 1103 patients assigned to warfarin (17.8 percent) and 176 of 1103 assigned to aspirin (16.0 percent; P=0.25; hazard ratio comparing warfarin with aspirin, 1.13; 95 percent confidence interval, 0.92 to 1.38). The rates of major hemorrhage were low (2.22 per 100 patient-years in the warfarin group and 1.49 per 100 patient-years in the aspirin group). Also, there were no significant treatment-related differences in the frequency of or time to the primary end point or major hemorrhage according to the cause of the initial stroke (1237 patients had had previous small-vessel or lacunar infarcts, 576 had had cryptogenic infarcts, and 259 had had infarcts designated as due to severe stenosis or occlusion of a large artery). CONCLUSIONS: Over two years, we found no difference between aspirin and warfarin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage. Consequently, we regard both warfarin and aspirin as reasonable therapeutic alternatives.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
Source: PubMed
Medical Details
The future of stroke treatment
Perttu J. Lindsberg MD, PhD ,Risto O. Roine MD, PhD ,Turgut Tatlisumak MD, PhD ,Tiina Sairanen MD ,Markku Kaste MD, PhD
Department of Neurology, University of Helsinki, Helsinki, Finland
Neurologic Clinics
Volume 18 • Number 2 • May 2000
Copyright © 2000 W. B. Saunders Company
Elucidation of the concept of the therapeutic window of opportunity in ischemic neuronal injury and understanding of the necessity of well-organized stroke services revolutionized the management of acute ischemic stroke during the last years of the second millennium. Thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA) within 3 hours from the onset of symptoms is an established therapy for selected patients. The challenge of stroke therapy at the outset of this millennium is to translate basic pathophysiologic evidence of ischemic neuronal injury into novel neuroprotective therapies either independently or combined with thrombolysis. Great hope is placed in the identification of pivotal molecular events in ischemic brain tissue and in the design of effective pharmacologic interventions to target them. Aggressive, invasive procedures are being developed, and therapies such as intraarterial clot lysis, hemicraniectomy, and mild hypothermia may improve the bleakest outcomes associated with the most severe forms of ischemic stroke, but their role must be rigorously evaluated. There is, however, no need to wait for future breakthroughs. The existing evidence strongly implies that good care of patients with stroke starts with organization of the entire stroke chain locally from the prehospital scene through the emergency room to the stroke unit. Without structured stroke services no pharmacologic or interventive therapy is likely to improve the outcome of the majority of stroke patients.
AURORA OF A NEW ERA
The last years of the previous millennium were revolutionary for the therapeutic possibilities of acute ischemic stroke. The approval of thrombolytic treatment with rt-PA as the first specific drug therapy for stroke has motivated efforts to organize stroke care in a more efficient way and enrolled emergency medical services (EMS) in closer cooperation with many stroke centers worldwide. Stroke is finally recognized as an emergency that can be treated. The reorganization of services is ongoing and may be one of the biggest challenges in the first decade of the new millennium. The still-limited but increasing fraction of stroke patients gaining benefit of thrombolytic therapy and other emergent care is highly dependent on this development.
On the basis of immense research on ischemic brain injury in experimental stroke models, elucidation of the evolving gene induction in brains harboring maturing infarcts has allowed grouping of sets of genes that are induced simultaneously or sequentially to define waves of gene expression and their consequences in ischemic tissue. Targeting these superimposed waves with interventions has allowed formulation of several putative therapeutic time windows. Recanalization of the occluded artery has so far been found to have a tight time window, but translation of the additional putative therapeutic windows into clinical practice still has not succeeded. The authors believe that the future will reveal several reasons for this. Although a major advance during the past decade has been the concept of a therapeutic window based on evolution of discrete molecular events in ischemic brain tissue, the authors believe that in the near future the utility of these windows will be demonstrated to the benefit of acutely paralyzed stroke patients at various phases of the disease.
The identification of superimposed waves of altered gene expression and its effects in ischemic brain tissue ( top) can translate into putative therapeutic windows in acute ischemic stroke in the future ( bottom). Presently, only the window of thrombolytic therapy is available for patients entering emergency rooms soon enough to benefit from any form of specific acute therapy. The near future may include first effective neuroprotective therapy, and considerable hope is placed on the combination of agents used once they are proven efficacious in respective therapeutic windows. Influencing one cascade of ischemic gene expression may prolong the therapeutic window for another molecular target of neuroprotection. Furthermore, focusing on the delayed effects occurring in the surviving neural networks may afford enhancement of the functional outcome. IEG = immediate early genes; HSP = heat shock (stress) proteins.
RECANALIZATION AND REPERFUSION
From the pathophysiologic point of view, the first target of therapy is limitation of ischemic injury by early reperfusion. In quantitative terms, critical hypoperfusion produced by an occluded artery accounts for a much larger proportion of the final infarct than secondary, cellular processes in the penumbral area and surrounding tissue. [36] Spontaneous recanalization of an occluded middle cerebral artery through intrinsic fibrinolytic activity is very common (25% to 70%), but often occurs too late to be beneficial. There is widespread enthusiasm about thrombolysis; but prudent skepticism also ensues. [13][14] Thrombolysis is already an approved treatment for acute ischemic stroke, so it is not discussed in this article. The balance between intravenous and intraarterial thrombolysis and a combination of both remains to be elucidated, especially after the publication of the Prolyse in Acute Cerebral Thromboembolism (PROACT) II results [27] (discussed elsewhere in this issue). Innovative techniques to lyse the clot are likely to gain more attention in the future. Microcatheters that use a saline flush and suction devices that use laser-induced ultrasound pulses, transcranial ultrasound, or other methods to enhance clot penetration or its dispersion mechanically are under development and likely to enter testing in humans.
New fibrinolytic and antiplatelet drugs are currently being developed for acute care of patients with stroke. It remains to be seen whether newer derivatives of tPA will be tested in large-scale trials after the approval rt-PA. Ancrod is a purified venom from the Malaysian pit viper that catalyzes the hydrolysis of fibrinogen, and leads to a sharp reduction of fibrinogen levels and has an anticoagulant effect and an effect on blood viscosity. The Stroke Treatment with Ancrod Trial (STAT) [72A] trial showed a significantly increased proportion of patients with normal Barthel index in the group treated with Ancrod, and this finding is likely to lead to a new trial on a larger scale. Glycoprotein IIb/IIIa-receptor antagonists, the third-generation platelet deaggregants, have been thoroughly tested in acute coronary syndromes and show a reduction of myocardial infarction and death up to 25% when used with heparin and aspirin, compared with aspirin and heparin alone. [87] At present, the monoclonal antibody abciximab is closest to phase III trials in acute stroke. Furthermore, other drugs such as nimodipine may enhance reperfusion by various mechanisms of action. [41] It seems obvious that fibrinolytic, anticoagulant, and antiplatelet agents will play a key role in future therapies of ischemic stroke.
PREVENTION OF ENDOTHELIAL ACTIVATION AND INFLAMMATION
Reperfusion
Injury
Thrombolysis
or spontaneous recanalization leads to tissue reoxygenation and formation of
free oxygen radicals and the influx of inflammatory cells. [9]
[35] This
so-called reperfusion injury is largely based on the interplay between the
endothelial cells and normal blood components on the resurgence of oxygen,
metabolism, and circulating factors of immune surveillance.
Endothelial
and blood-brain barrier injury.
The
endothelium is an antithrombotic and antiadhesive organ under normal
homeostasis, which is challenged during ischemia and subsequent reperfusion
(I/R), allowing it to express adhesion molecules and chemotactic factors. This
transformation attracts and activates platelets and neutrophils to adhere to
the endothelium and to emigrate into the brain parenchyma in large quantities.
[35] [50]
The capillary blood flow is impaired by plugging neutrophils, which also
secrete proteolytic enzymes and cytokines when activated. [35]
Cell membrane lipids are broken down by phospholipase A2 to release
to arachidonic acid. Increased arachidonic acid metabolism leads to the
production of proinflammatory and vasoactive eicosanoids (thromboxane,
leukotrienes, and prostaglandins) by the enzymatic activity of
cyclooxygenase-2 (COX-2) and lipooxygenase. [22]
To control reperfusion injury associated with the above-mentioned phenomena,
the therapeutic approaches closest to clinical application include lipid
peroxidation reducing agents, free radical scavengers, [8]
[17][83][90] and
agents that block the endothelium-neutrophil adherence, which bind to specific
adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on the
endothelium [72]
or its ligands on leukocytes.
Considerations
on future treatments to prevent reperfusion injury.
A
growing number of studies have already indicated that pharmacologic
interventions aimed at inhibiting the actions of polymorphonuclear leukocytes
can rescue neuronal tissue after ischemia in therapeutic protocols given to
experimental animals. [48]
Together with evidence based on experimental models of myocardial injury, [21]
this line of research has promised therapeutic possibilities to restrict
tissue injury after ischemia and reperfusion. It should be kept in mind that,
besides endothelium, ICAM-1 molecules are present on leukocyte membranes and
even during acute stroke they may serve essential homeostatic and host defense
functions. An important task for the forthcoming studies is to elucidate
whether specific blocking of ICAM-1-dependent leukocyte binding in the
ischemic region is sufficient, or is blocking of binding based on other
upregulated adhesion molecules such as endothelial leukocyte adhesion
molecule-1 (E-selectin, ELAM-1) and vascular cell adhesion molecule-1 (VCAM-1)
also necessary. Some investigations have reported substantial increases in E-selectin
messenger RNA in the area of focal brain infarction in rats subjected to
permanent middle cerebral artery occlusion. [4]
Future drug development should overcome the recently discovered unwanted
neutrophil coactivating properties of the antiadhesion monoclonal antibodies
already tested in the clinical setting of stroke. [89]
The failure to show a beneficial effect of antiadhesion treatment in the
clinical enlimomab study of stroke [72]
should not discourage further clinical investigation of this complex but
therapeutically interesting pathophysiologic cascade.
The
authors have demonstrated that the leukocyte infiltration is a relatively
prolonged phenomenon in humans, [50]
as opposed to the more acute and transient peaking at 12 to 24 hours in the
ischemic infarction in rats. [28]
Moreover, the ICAM-1 upregulation seems prolonged in human middle cerebral
artery infarction, lasting for several days as opposed to a few hours in the
transient middle cerebral artery occlusion in primates. [50]
[61] With
additional studies demonstrating increased expression of adhesion molecules
clinically in stroke, [16]
[23] [47]
this evidence underscores the potential usefulness of this adhesion
interaction as a target of intervention in human subjects and promotes the
concept that a treatment protocol lasting several days is necessary to cover
the period during which ICAM-1 expression is upregulated and polymorphonuclear
cells accumulate in the ischemic area.
In
small animal and primate models, free radical formation and depletion of
endogenous antioxidants occur during both permanent and temporary ischemia and
aggravate the ischemic injury. Antioxidants (free radical scavengers)
attenuate both cytotoxic and vasogenic brain edema, facilitate
re-establishment of Ca2+ homeostasis, and antagonize glutamate
excitotoxicity and, thus, may alleviate the injury caused by free radicals.
Free radical scavengers with potentially protective effects include superoxide
dismutase (SOD), catalase, glutathione, iron chelators, vitamin E, alphaphenyl
nitrogen (PBN), dimethylthiourea (DMTU), oxypurinol, tirilazad mesylate, and
lazaroids. Superoxide dismutase was shown to reduce infarct volume in
transgenic mice. [90]
Tirilazad mesylate was investigated in a multinational phase III trial in
subarachnoidal hemorrhage [44]
and was shown to significantly reduce mortality and improve functional
outcome; however, a review of all tirilazad trials in ischemic stroke found no
benefit. [8]
Ebselen is another inhibitor of lipid peroxidation that reduces infarct size
in rats subjected to temporary focal ischemia. Oral ebselen therapy for 2
weeks initiated within 48 hours after stroke onset improved outcome at 30
days. [90]
Polyethylene glycolated superoxide dismutase (PEG-SOD), another free radical
scavenger, significantly improved the outcome in patients with severe head
injury [58]
in a phase II trial. Spin traps or other free radical scavengers that readily
penetrate into the brain may impart even greater protection than tirilazad or
PEG-SOD, which work primarily within the vasculature.
In
addition to shared molecular mechanisms of ischemic brain damage, future
research may reveal subtle differences in their expression across different
mammalian species. In human ischemic stroke, sequential appearance of
proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha)
immunoreactivity (Sairanen, unpublished data) with COX-2, the key enzyme of
prostanoid synthesis, is supported by work from the authors' laboratory. [67]
Neuronal and glial COX-2 induction was evident early (15 to 24 hours) in the
periinfarct areas; it was subsequently (1.2 to 6.3 days) prominent in the
neurons of the infarct core and the contralateral hemisphere, and thereafter
(8.5 to 18 days) persisted predominantly in the contralateral, surviving
hemisphere. [67]
With well-tolerated agents available, interventions targeted to inducible
factors such as cytokines or COX-2 during the injury propagation phase solely
could translate into future stroke therapies.
PHARMACOLOGIC NEUROPROTECTION
Neuroprotection
means enhancing the tolerance of brain cells against ischemia. Neuroprotection
is afforded by affecting one or more biochemical and metabolic consequences of
ischemia and protecting at least part of the compromised brain tissue from
evolving into infarction. [26]
Neuroprotective drugs should be available for intravenous administration, and
thus, should be soluble in standard solvents. In the clinical setting, a rapid
distribution of the neuroprotective agent to the brain would be desirable to
maximize drug concentrations in poorly perfused ischemic tissue as rapidly as
possible after stroke onset. [32]
As our understanding of the pathophysiologic processes of brain ischemia
evolved, it became feasible to develop targeted therapies to single steps in
the ischemic cascade to be tested initially in experimental animals.
One
of the major achievements within the past decades has been the elucidation of
a concept of therapeutic windows of opportunity in ischemic neuronal injury
. Looking
back, the research on the effect of the calcium entry blocking drug nimodipine
on ischemic neuronal injury is an illustrative example. After promising
results in experimental animal models of stroke, relatively sizable clinical
trials were launched that showed initial promising results. [29]
The disappointment was immense when eventually no clinical benefit could be
demonstrated. [45]
[82] A new
trial was launched to investigate whether nimodipine still might have a
neuroprotective effect within 6 hours after symptom onset (Very Early
Nimodipine Use in Stroke [VENUS]), but the interim results of this trial did
not encourage the investigators to enroll the originally planned 1500
patients. Despite its unproven efficacy in ischemic stroke, nimodipine is
still the only proven compound that can, in fact, prevent ischemic brain
damage in the setting of aneurysmatic subarachnoid hemorrhage, where it
significantly diminishes disability from delayed ischemic infarcts caused by
vasospasm and is routinely used for this indication. [24]
The authors believe that this finding relates to the concept of therapeutic
window, as nimodipine is onboard already before any ischemic damage or spasm
has set in. Nimodipine is currently indicated in the treatment of subarachnoid
hemorrhage but not in acute ischemic stroke.
Inhibition of Calcium Influx
Focal
brain ischemia is associated with cell membrane depolarization and a massive
increase of excitatory amino acids, glutamate, and aspartate. [74]
These substances bind to receptors (e.g., N-methyl-D-aspartate [NMDA]- and
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA]-receptors)
that gate important ion channels, so the increase in the agents leads to an
excessive influx of calcium (Ca2+ ), sodium (Na+ ),
chloride, and water into the neurons and an efflux of potassium (K+
) into the extracellular space. [76] [77>] Among
these ion changes, the massive influx of Ca2+ is detrimental and in
part responsible for neuronal death. [77]
Calpains are calcium-activated proteolytic enzymes that are activated during
cerebral ischemia and degrade cytoskeletal proteins such as spectrin. Calpain
inhibitors AK275, AK295, and MDL 28,170 significantly decreased infarct size
in rat ischemia models. [6]
[7] [54]
In these studies, MDL 28,170 was initiated 6 hours and AK275 3 hours after
middle cerebral artery occlusion. These results support the contention that
inhibiting downstream consequences of ischemia-induced intracellular Ca2+
accumulation may provide a second, delayed window of therapeutic opportunity.
The NMDA receptor includes a glycine binding site, the activation of which is
essential for NMDA-receptor functioning. Glycine site antagonists have
antiischemic properties. [63][79][81]
A glycine site antagonist (GV150526A) is in phase III trials. This compound
showed no significant cardiovascular side effects and no psychotomimetic
action in phase II trials. Among the NMDA antagonists, magnesium sulfate was
found to be safe, improved functional outcome, and slightly reduced mortality
in a small study. [57]
A multicenter phase III study is recruiting patients. YM872, a novel AMPA-receptor
antagonist, was found to be neuroprotective in animal models [74]
and is currently under clinical development. [59]
Inhibition of Protein Synthesis
Apoptosis or programmed cell death is an active cellular process that requires novel gene induction, cell metabolism, and protein synthesis, and occurs late after an ischemic insult. Specific receptors on the neuronal membrane should be stimulated for apoptosis to be initiated. [2] Agents that may block the synthesis of proteins participating in apoptosis have reduced tissue injury significantly in focal and global ischemia models. [33] [73] Caspases play central role in apoptosis [84] and caspase inhibition was recently found to reduce significantly ischemic injury in mice. [20] A recent study showed that activation of metabotropic glutamate receptors rapidly reverse the apoptotic processes. [88] Apoptosis might be suppressed by growth factors and protein synthesis inhibitors. This suppression may, in part, account for the efficacy of growth factors in experimental stroke models. The contribution of apoptosis to human stroke and the eventual functional benefit of its inhibition require further work.
Prophylactic Neuroprotection
Certain invasive procedures are associated with an identifiable, substantial risk for stroke. Such procedures include coronary artery bypass graft, valve replacement, cardiac transplant, carotid endarterectomy, aneurysmectomy, resection of arteriovenous malformations, and endovascular therapy. Patients undergoing these procedures have a defined risk period, and short-term neuroprotection, initiated before the procedure with a neuroprotective agent that does not interfere with the procedure, is attractive. This approach requires that safe, efficacious, orally available, and relatively inexpensive neuroprotective drugs will be developed. [26] Ideally, neuroprotective properties would be combined into drugs used in maintenance therapy of common risk factors of stroke such as hypertension or hypercholesterolism. Eventually, a preemptive neuroprotective therapeutic window for patients in certain risk groups could be identified
HYPOTHERMIA AND HEMICRANIECTOMY IN MALIGNANT MIDDLE CEREBRAL ARTERY INFARCTION
Up
to 10% of patients presenting with acute stroke will develop a
life-threatening, malignant middle cerebral artery infarction, in which a
mortality rate of up to 80% has been reported. [10][34] Death
by herniation is usually the result of cerebral edema, which leads to raised
intracranial pressure, reduced consciousness, and the need of intubation and
ventilator support. Total middle cerebral artery infarction per se has a much
lower mortality, usually below 30%. Antipyretic treatment; careful control of
fluid balance, blood glucose, and blood gas levels; and positioning can in
many cases prevent the development of life-threatening edema. Osmotherapy
(especially glycerol, possibly followed by hexaethylstarch in hypertonic
saline) is sometimes effective in reversing the edema, but many cases are
unresponsive to conventional therapy. Hyperventilation and steroids are
potentially harmful and generally contraindicated. Mild induced hypothermia
and hemicraniectomy represent two novel experimental forms of therapy for
patients with malignant middle cerebral artery infarctions.
Hypothermia
It
has been appreciated for decades that profound systemic hypothermia lowers
metabolic rate and is useful for organ protection during cardiovascular and
neurosurgical procedures. The neuroprotective effect of mild hypothermia of
only two degrees was not confirmed experimentally until in 1987 in a landmark
study from Ginsberg's laboratory. [12]
In fact, mild hypothermia exerts a more powerful protective effect than most
neuroprotective agents studied, the effect of which, at least in some cases
(MK-801), was found to be more or less explained by hypothermia itself. There
is now uniform experimental evidence that hypothermia is protective after
global and focal hypoxic injury to the brain. [12]
[30] [49]
The mechanisms of action of hypothermia are multiple and, in fact, better
known than those of many neuroprotective agents. Hypothermia decreases
metabolism, retards depletion of high-energy phosphates, inhibits the release
of excitatory neurotransmitters and free fatty acids, inhibits various enzymes
including CaM kinase II and the expression of heat shock proteins, oxygen
radical production, prevents leukocyte accumulation, preserves postischemic
protein synthesis and protein kinase C activity, and preserves the blood-brain
barrier and cellular membranes from ischemia-induced disruption. [31]
Recent
clinical evidence for the importance of temperature in acute ischemic stroke
is rather convincing, although the therapeutic efficacy of induced hypothermia
remains to be proved. In 1995, fever during the first week after infarct was
shown to be an independent predictor of poor outcome. [3]
The next year, Reith and coworkers from Copenhagen demonstrated, in a
prospective study of 390 stroke patients, lower mortality and better outcome
in patients with spontaneous mild hypothermia (<36.5°C) on admission,
regardless of initial stroke severity. On admission, 11% of the patients were
hypothermic (<36.5°C), 64% were normothermic (36.5-37.5°C), and 25% were
hyperthermic (>37.5°C). For each 1°C increase in body temperature, the
relative risk of poor outcome rose by 2.2 (95% confidence interval 1.4-3.5, P < 0.002). [63]
Furthermore, Davalos and Castillo [15]
have shown that hyperthermia is associated with early neurologic deterioration
and increased release of glutamate in the cerebrospinal fluid, thus linking
excitoxicity with hyperthermia in human stroke. Mild therapeutic hypothermia
has already been tested in clinical trials in global cerebral ischemia (brain
injury and cardiac arrest). [18]
[53] In a
small feasibility study, Schwab et al, [71]
in 1998, induced mild hypothermia reduced elevated intracranial pressure in
malignant middle cerebral artery infarction sharply but temporarily and was
associated with a mortality rate of 44%, considerably lower than expected with
conventional therapy in the same center. The rate of rewarming is probably of
crucial importance, because rapid rewarming has a rebound effect on
intracranial pressure. Induced mild hypothermia of 33°C to 34°C for 24 hours
requires relaxed general anesthesia and intensive care with careful monitoring
and cannot be recommended until its safety and efficacy have been confirmed by
a larger scale multicenter studies, currently being planned both in the United
States and in Europe. In ongoing and completed clinical trials, no excess of
arrhythmias, bleeding, or infection has been reported in patients treated with
mild hypothermia.
Although
induced hypothermia is not an established therapy, most stroke centers
actively control body temperature to prevent any degree of fever, especially
during the acute stage and in cases of elevated intracranial pressure.
Patients with focal or global cerebral ischemia are often slightly hypothermic
when found and should not be rewarmed by the emergency medical services
providers. At present, the most feasible cooling method may be external total
body cooling with blankets and airflow; however, faster induction and
especially devices for prehospital use would be highly desirable.
Hemicraniectomy
Hemicraniectomy,
in which the edematous, infarcted brain is surgically decompressed, is
advocated by a few stroke centers as a novel therapy for malignant middle
cerebral artery infarction. Surgical management consists of removing a large
frontoparietal-occipital bone flap, opening of the dura, and placing a wide
dural graft. The trepanation extends over the sagittal sinus to prevent
compression of ipsilateral dural veins at the edge of the trepanation.
Resection of infarcted tissue is not recommended. The original or artificial
bone flap will be replaced several weeks after surgery. The overall rate of
perioperative complications has been reported to be 10%. The largest series of
patients treated with hemicraniectomy for malignant cerebral infarction was
reported in 1998 from Heidelberg. [71]
The outcome of 31 patients treated with early hemicraniectomy (less than 24
hours) was compared with historical controls as reported by Rieke and with
patients operated on late (more than 24 hours after stroke). [65]
The hemicraniectomy patients had a mortality of 34.4% when treated late and
16% when operated on early, as compared with a mortality rate of 80% in
historical controls, who were also older. In addition to the decreased
intracranial pressure, hemicraniectomy also may lead to mild local hypothermia
of the exposed brain. Nevertheless, the survival rate was higher in patients
undergoing hemicraniectomy than in patients treated by systemic hypothermia,
as reported by the same center. [70A] [71]
The optimal timing of hemicraniectomy is unclear, because many patients
respond to conservative care; the surgical option probably should be reserved
for patients with a truly malignant course. On the other hand, early
decompressive surgery seems to have a more favorable effect. Better patient
selection and reliable prognostic factors are still needed, because the
malignant course cannot be reliably predicted. In some centers, hypothermia
and hemicraniectomy are used as alternative treatments. Randomized controlled
trials are necessary to clarify the place of hemicraniectomy as they are with
hypothermia.
FACILITATION OF BRAIN REPAIR MECHANISMS
One reason for the limited clinical success in translating basic pathophysiologic data and therapeutic windows elucidated in experimental stroke models might turn out to be overlooking some important aspects of the natural course of ischemic stroke. The surviving brain itself is responsible for the considerable functional recovery seen in patients during the first days after the ischemic event, when many genes regulating the trophic effects that govern neuronal growth, sprouting, and synapse formation are induced. Augmentation of this process has not been a major therapeutic target so far, but will probably become so in the future. Independent of the infarct size, restorative therapies could significantly enhance the recovery by promoting functional compensation by surviving brain areas, stimulated neuronal sprouting, and novel synaptic connections, and other strategies affecting brain plasticity
Enriched Environment
An
enriched environment that allowed the performance of various tasks after a
brain insult was shown to facilitate functional recovery when rats were placed
in the enriched environment immediately after the ischemic insult [43]
and even when the transfer was delayed for 2 weeks, [42]
suggesting that a rich environment may stimulate mechanisms that enhance brain
plasticity and better functional recovery. Similar approaches have already
been incorporated into rehabilitative attempts and are used in stroke units.
Paradoxically, surviving tissue in the injured hemisphere may be fatally
vulnerable to excessive behavioral demand. [68]
If the impaired limb is overused while the intact limb is restricted by a
cast, injury size is greatly increased and recovery of function is severely
disrupted. [68]
The use-it-or-lose-it rehabilitative approach is popular, but an over
aggressive strategy should be avoided.
Growth Factors
Endogenous
growth factors may provide neuroprotection acutely and enhance neuronal
sprouting later. Unlike other growth factors, basic fibroblast growth factor (bFGF)
penetrates the brain. Probably because of this penetration, it is the most
widely studied growth factor. bFGF reduces infarct size acutely without an
effect on cerebral blood flow [80]
and improves functional outcome in chronically treated rats. [46]
A phase II trial showed that bFGF is well tolerated in stroke patients, and
phase III trials were started in the United States and Europe. The American
trial was stopped, probably because of safety reasons. There were no safety
concerns in the European trial, but it still is on hold. Unfortunately, these
trials were not designed to investigate whether the putative delayed
therapeutic window, [46]
aiming at enhancement of the spontaneous restorative brain processes, can be
used clinically
. Other growth factors have shown neuroprotective effects in in vitro and in
vivo experiments, and clinical studies with novel approaches will probably
follow.
Neural Transplantation
The
studies using neural transplants to alleviate the effects of ischemic brain
damage were initiated in the 1980s. In models of middle cerebral artery
occlusion models in rats, fetal grafts were shown to survive and receive
extensive innervation from the host, although the functional effects of the
grafts in alleviating cognitive and sensorimotor deficits remain uncertain. [37]
Neuronal stem cells have been shown to improve stroke recovery in rats, and
this procedure will be an area of growing interest as preliminary human
studies are already being planned.
COMBINATION THERAPIES
The
rationale for combination therapy is based on the increasing knowledge of the
pathophysiologic mechanisms of ischemic brain damage. Given the complex
mechanisms involved in the ischemic cascade, it seems unlikely that any single
neuroprotective agent is able to cover the whole cascade. None of the
neuroprotectants so far tested in acute ischemic stroke in humans has been
shown to be effective, which also has prevented effective testing of the
combination approach in humans.
The
only currently available treatment for acute ischemic stroke, thrombolysis,
can induce further tissue damage through mechanisms involved in reperfusion
injury, hemorrhagic conversion, and frank parenchymal hemorrhage, that
partially or totally eliminates the benefits of reperfusion itself. Combining
neuroprotection with thrombolysis may decrease or eliminate the untoward
effects of reperfusion.
Even
if a neuroprotectant agent could keep neurons alive, the ischemic penumbra
would remain functionally inert until reperfusion (spontaneous or induced)
enables the cerebral blood flow to rise over the threshold of electric
failure. The presence and the extent of the ischemic penumbra are time
dependent. The longer the hypoperfusion exists, the higher residual flow that
is needed to keep neurons alive. The threshold of ATP depletion is 0.13 mL/g
brain tissue/min after 30 minutes, and it increases to 0.19 mL/g brain
tissue/min after 2 hours, to 0.23 mL/g brain tissue/min after 6 hours, and to
0.32 mL/g brain tissue/min after 12 hours of arterial occlusion, where
neuronal death occurs at levels of cerebral blood flow close to normal values.
[40]
Spontaneous reperfusion does occur, [25]
but the rate and timing are unpredictable and unlikely to allow for neuronal
survival before reperfusion. [39][56][66][92] In
combination therapy, the time before treatment has probably the largest impact
on the outcome of a patient. The combination strategy has however, many good
reasons why it could be more effective than any single therapy.
Mechanisms of Action of Combination Therapies
Each agent affects only one of the several mechanisms in the ischemic cascade, whereas a combination therapy affects several points in the cascade.
Neuroprotective agents, if shown to be safe, can be administered prior to CT or MR imaging and possibly could be given by paramedics before the arrival in the hospital.
Neuroprotective agents, if administered very early after the infarct, may prolong the time interval that the brain can tolerate ischemia before reperfusion. These agents may extend the time window for thrombolysis when collateral perfusion carries the neuroprotective agents to the ischemic penumbra.
Neuroprotective agents connected with successful thrombolysis may avoid or reduce reperfusion injury of severely or irreversibly damaged brain tissue.
Thrombolysis and neuroprotective agents may act synergistically and may result in a more complete attenuation of ischemic damage and better functional outcome than either of the two treatments alone.
Combination therapy strategies that have been effective in experimental stroke are
- Antiexcitotoxic and antiapoptotic strategies, [19] [52]
- Antiexcitotoxic and free radical scavenger strategies, [5]
- Antiexcitotoxic and calcium channel blocker strategies, [85]
- Antiexcitotoxic and gamma-amino-butyric acid (GABA) agonist strategies, [51]
- Antiexcitotoxic and phosphatidylcholine precursor strategies, [62]
- Calcium antagonist and free radical scavenger strategies, [69]
- Blood substitute and neuroprotective agent strategies, [1]
- Thrombolysis and antiexcitotoxic strategies, [94]
- Thrombolysis and free radical scavenger strategies, [55]
- Thrombolysis and antiinflammatory strategies, [11] [93]
- Thrombolysis and thromboxane A2 antagonist strategies, [86]
- Thrombolysis and antiplatelet therapy strategies, [38] and
- Thrombolysis and two or more neuroprotective agents with different or additional properties.
A combination of thrombolysis plus two or more neuroprotective interventions with different or additional properties has not been studied in experimental animals. There is currently no evidence whether mild therapeutic hypothermia could be effectively combined with any other neuroprotective or recanalizing strategy. Lowering the temperature also might be feasible either in the hyperacute stage to buy time before more specific therapy can be instituted or perhaps later in case of elevated intracranial pressure. Multifaceted treatment is likely to be the state of the art stroke therapy in the future. These cocktails could include prehospital antiexcitotoxic and calcium antagonist therapies, early thrombolysis on arrival combined with free radical scavenger and antiinflammatory therapies, or antiapoptotic and growth factor therapies. Importantly, even the narrow therapeutic window of thrombolysis has recently been found to be extended by antiinflammatory combination therapy in animal experiments. [93] Eventually, the entire therapeutic intervention should be initiated before admission to the hospital and should probably be extended until after hospital discharge; in other words, the entire therapeutic intervention would take weeks.
ORGANIZATION OF STROKE SERVICES
The chain of survival concept, originally for designed for out-of-hospital cardiac arrest, is valid for stroke too. If one link of the chain fails, the results of stroke management will be disappointing. Educational campaigns targeted to the public are mainly aimed at triggering immediate activation of emergency medical services by using a uniform dispatch center access code. Stroke can be rapidly recognized by dispatch center operators using simple key words. Stroke deserves a high priority and a high urgency code. The entire staff of the emergency medical system must be educated for recognition and care of stroke. At present, stroke is not a high priority call in most emergency medical systems, but the elevation of stroke priority has already been implemented in many cities worldwide.
Successful and cost-effective management of stroke according to current and future guidelines is only possible in well-organized stroke centers. Therefore, the care of stroke is likely to concentrate in large centers that serve a population of one million or more. Cost-effective stroke care will be a problem in scarcely inhabited areas, except when covered by helicopter services. Several stroke center recommendations, including those by the National Stroke Association and the European Stroke Initiative (EUSI), have been published or are in preparation. Stroke teams and stroke units are often viewed as alternative approaches, but they can be used simultaneously. The emergency room staff is part of the stroke team. On admission, there should be a second triage to identify stroke patients with extremely urgent condition, who should receive an emergent stroke code. The minimum requirements for optimal stroke care are the 24-hour availability of a neurologist and a nurse who specialize in care of stroke patients, neurosurgeon, laboratory services, and neuroimaging (CT, MR imaging, and ultrasonography). The care is based on written protocols and guidelines to minimize delays. The "door-to-needle time" must be kept below 60 minutes, by which time the brain scans also must have been performed and analyzed. After emergent diagnostics and therapy, the patient is transferred to an acute stroke unit with dedicated staff, preferably within 3 hours, to minimize complications, progression, and recurrence of ischemia. The efficacy of specialized multidisciplinary stroke units in reducing death and disability is proven [77] and will probably not be challenged in the future.
SUMMARY
Thrombolysis with rt- PA has been shown to be a safe and effective therapy. In acute ischemic stroke within 3 hours from the onset of symptoms. [60] In the future, other therapies will be available to be used independently and in combination with rt-PA and other neuroprotective agents. The authors believe that translation of neuroprotective pharmacotherapy to target induction of pivotal gene sets or receptors will soon meet clinical success. Mild therapeutic hypothermia is currently the most promising nonpharmacologic approach available. It remains to be seen whether more invasive and more aggressive monitoring and treatment methods, including neurosurgery, will be more significant in future management of acute ischemic stroke. Finally, none of these methods or their combinations is likely to work unless there is a structured stroke center organization, involving the entire chain of emergent and acute care, right from the prehospital scene and dispatch center to the emergency room and stroke unit, capable of providing fast and efficient care throughout. Without the above-mentioned conditions, no drug therapy is likely to have a major impact on stroke recovery now or in the foreseeable future.
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